Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity

ABSTRACT

Compounds of the formula                    
     where the symbols have the meaning described in the application, have retinoid-like or retinoid antagonist-like biological activity.

CROSS REFERENCE TO THE RELATED APPLICATION

The present invention is a divisional of application Ser. No.09/550,952, filed on Apr. 17, 2000, now abandoned, which is a divisionalof application Ser. No. 09/057,386 filed of Apr. 8, 1998 now U.S. Pat.No. 6,117,987, which is a divisional of application Ser. No. 08/667,663filed on Jun. 21, 1996, now issued as U.S. Pat. No. 5,773,594.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds having retinoid and/orretinoid antagonist-like biological activity. More specifically, thepresent invention relates to alkyl or aryl substituteddihydronaphthalene derivatives which bind to retinoid receptors and haveretinoid-like or retinoid antagonist-like biological activity.

2. Background Art

Compounds which have retinoid-like activity are well known in the art,and are described in numerous United States and other patents and inscientific publications. It is generally known and accepted in the artthat retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and is diseases associated with human papilloma virus(HPV), including warts and genital warts, various inflammatory diseasessuch as pulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other, agents such as Minoxidil^(R), diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis.

U.S. Pat. Nos. 4,740,519 (Shroot et al.), 4,826,969 (Maignan et al.),4,326,055 (Loeliger et al.), 5,130,335 (Chandraratna et al.), 5,037,825(Klaus et al.), 5,231,113 (Chandraratna et al.), 5,324,840(Chandraratna), 5,344,959 (Chandraratna), 5,130,335 (Chandraratna etal.), Published European Patent Application Nos. 0 176 034 A (Wuest etal.), 0 350 846 A (Klaus et al.), 0 176 032 A (Frickel et al.), 0 176033 A (Frickel et al.), 0 253 302 A (Klaus et al.), 0 303 915 A (Bryceet al.), UK Patent Application GB 2190378 A (Klaus et al.), GermanPatent Application Nos. DE 3715955 A1 (Klaus et al.). DE 3602473 A1(Wuest et al., and the articles J. Amer. Acad. Derm. 15: 756-764 (1986)(Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo et al.), J.Med Chem. 1988 31, 2182-2192 (Kagechika et al.), Chemistry and Biologyof Synthetic Retinoids CRC Press Inc. 1990 p 334-335, 354 (Dawson etal.), describe or relate to compounds which include a tetrahydronaphthylmoiety and have retinoid-like or related biological activity. U.S. Pat.No. 4,391,731 (Boller et al.) describes tetrahydronaphthalenederivatives which are useful in liquid crystal compositions.

Published European Patent application Nos. 0 661 259 A1 and 0 661 261 A1(Bristol-Myers Squibb) describe further dihydronaphthalene andnaphthalene derivatives which are said in the disclosures to haveretinoid-like biological activity.

U.S. Pat. Nos. 4,980,369, 5,006,550, 5,015,658, 5,045,551, 5,089,509,5,134,159, 5,162,546, 5,234,926, 5,248,777, 5,264,578, 5,272,156,5,278,318, 5,324,744, 5,346,895, 5,346,915, 5,348,972, 5,348,975,5,380,877, 5,399,561, 5,407,937, (assigned to the same assignee as thepresent application) and patents and publications cited therein,describe or relate to chroman, thiochroman and1,2,3,4-tetrahydroquinoline derivatives which have retinoid-likebiological activity. Still further, several co-pending applications andrecently issued patents which are assigned to the assignee of thepresent application, are directed to further compounds havingretinoid-like activity.

Although pharmaceutical compositions containing retinoids have wellestablished utility (as is demonstrated by the foregoing citation ofpatents and publications from the voluminous literature devoted to thissubject) retinoids also cause a number of undesired side effects attherapeutic dose levels, including headache, teratogenesis,mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skinirritation, headache and hepatotoxicity. These side effects limit theacceptability and utility of retinoids for treating disease.

It is now general knowledge in the art that two main types of retinoidreceptors exist in mammals (and other organisms). The two main types orfamilies of receptors respectively designated the RARs and RXRs. Withineach type there are subtypes; in the RAR family the subtypes aredesignated RAR_(α), RAR_(β) and RAR_(γ), in RXR the subtypes are:RXR_(α), RXB_(β) and RXR_(γ). It has also been established in the artthat the distribution of the two main retinoid receptor types, and ofthe several sub-types is not uniform in the various tissues and organsof mammalian organisms. Moreover, it is generally accepted in the artthat many unwanted side effects of retinoids are mediated by one or moreof the RAR receptor subtypes. Accordingly, among compounds havingagonist-like activity at retinoid receptors, specificity or selectivityfor one of the main types or families, and even specificity orselectivity for one or more subtypes within a family of receptors, isconsidered a desirable pharmacological property. Some compounds bind toone or more RAR receptor subtypes, but do not trigger the response whichis triggered by agonists of the same receptors. A compound that binds toa biological receptor but does not trigger an agonist-like response isusually termed an antagonist. Accordingly, the “effect” of compounds onretinoid receptors may fall in the range of having no effect at all,(inactive compound, neither agonist nor antagonist), the compound mayelicit an agonist-like response on all receptor subtypes (pan-agonist),or a compound may be a partial agonist and/or partial antagonist ofcertain receptor subtypes if the compound binds to but does not activatecertain receptor subtype or subtypes but elicits an agonist-likeresponse in other receptor subtype or subtypes. A pan antagonist is acompound that binds to all known retinoid receptors but does not elicitan agonist-like response in any of the receptors.

It has been recently discovered and described in a pending applicationassigned to the same assignee as the present application that retinoidantagonist-like activity of a compound is also a useful property, inthat such antagonist compounds can be utilized to block certainundesired side effects of retinoids, to serve as antidotes to retinoidoverdose or poisoning, and may lend themselves to other pharmaceuticalapplications as well. More particularly, regarding the publishedscientific and patent literature in this field, published PCTapplication WO 94/14777 describes certain heterocyclic carboxylic acidderivatives which bind to RAR retinoid receptors and are said in theapplication to be useful for treatment of certain diseases orconditions, such as acne, psoriasis, rheumatoid arthritis and viralinfections. A similar disclosure is made in the article by Yoshimura etal. J Med. Chem. 1995, 38, 3163-3173. Kaneko et al. Med. Chem Res.(1991) 1:220-225; Apfel et al. Proc. Natl. Acad. Sci. USA Vol 89 pp7129-7133 Augusty 1992 Cell Biology; Eckhardt et al. Toxicology Letters,70 (1994) 299-308; Keidel et al. Molecular and Cellular Biology, Vol 14,No. 1, Jan. 1994, p 287-298; and Eyrolles et al. J. Med. Chem. 1994, 37,1508-1517 describe compounds which have antagonist like activity at oneor more of the RAR retinoid subtypes.

SUMMARY OF THE INVENTION

Among the compounds of Formulas 1 through 6, the present inventioncovers the compounds of Formula 6. Compounds of the remaining formulasare disclosed here inasmuch as the methods of their synthesis pertainsto the best modes of the presently contemplated synthetic routes leadingto the compounds of Formula 6. Thus the present invention pertains tocompounds of Formula 6.

wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkyl of 1 to6 carbons, and n is an integer between 0 and 2;

X₂ is

S or O;

Z is

—N═N—,

—N(O)═N—

—N═N(O)—,

—N═CR₁—,

—CR₁═N,

—(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

—CO—NR₁—,

—CS—NR₁—,

—NR₁—CO,

—NR₁—CS,

—COO—,

—OCO—;

—CSO—;

—OCS—;

—CO—CR₁═CR₁—;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,or alkylthio of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

R₄ is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons andhaving 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkyl-naphthyl,phenyl-C₁-C₁₀alkyl, napthyl-C₁-C₁₀alkyl; CN, or (CH₂)_(p)CO₂R₈ where pis an integer between 0 to 10;

R₅ is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 doublebonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl,C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀alkyl,napthyl-C₁-C₁₀alkyl; Si(C₁₋₆alkyl)₃, COR₁₄ camphanoyl, C(R₁₅)(R₁₆)X₂R₁₇;

Y is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y represents adirect valence bond between said (CR₂═CR₂)_(n′) group and B;

A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkyllphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons;

R₁₄ is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbonsand having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to3 triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl,phenyl-C₁-C₁₀alkyl, napthyl-C₁-C₁₀alkyl, and

R₁₅ and R₁₆ are hydrogen or lower alkyl of 1 to 6 carbons, R₁₇ is loweralkyl of 1 to 6 carbons, or R₁₆ and R₁₇ jointly form a ring having atotal of 4 to 5 carbons and the X₂ heteroatom;

compounds of Formula 2

wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkyl of 1 to6 carbons, and n is an integer between 0 and 2;

X₂ is

S or O;

Z is

—N═N—,

—N(O)═N—,

—N═N(O)—,

—N═CR₁—,

—CR₁═N,

—(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

—CO—NR₁—,

—CS—NR₁—,

—NR₁—CO,

—NR₁—CS,

—COO—,

—OCO—;

—CSO—;

—OCS—;

—CO—CR₁═CR₁—;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,or alkylthio of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

Y is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or S then Y represents adirect valence bond between said (CR₂═CR₂)_(n′) group and B;

A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons, and

R₁₈ is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10carbons, or the two R₁₈ groups jointly form a ring having a total of 3to 6 carbons, or the two X₂R₁₈ groups jointly symbolize an oxo (═O) or athio (═S) function, or each of the two X₂R₁₈ groups is H;

compounds of Formula 3

wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkyl of 1 to6 carbons, and n is an integer between 0 and 2;

Z is

—N═N—,

—N(O)═N—,

—N═N(O)—,

—N═CR₁—,

—CR₁═N,

—(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

—CO—NR₁—,

—CS—NR₁—,

—NR₁—CO,

—NR₁—CS,

—COO—,

—OCO—;

—CSO—;

—OCS—;

—CO—CR₁═CR₁—;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,or alkylthio of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

Y is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting or pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂

when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y represents adirect valence bond between said (CR₂═C₂)_(n′) group and B;

A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons, and

R₁₉ is independently hydrogen, alkyl of 1 to 10 carbons,fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbonsand having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to3 triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl,phenyl-C₁-C₁₀alkyl, naphthyl-C₁-C₁₀alkyl; heteroaryl selected from thegroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, further R₁₉ is independently CN, CHO, CH(OR₁₂)₂, CHOR₁₃O,(CH₂)_(p)CO₂R₈, (CH₂)_(p)CH₂OH, (CH₂)_(p)CH₂OR₁₁, (CH₂)_(p)CH₂OCOR₁₁,where p is an integer between 0 to 10, or the two R₁₉ groups jointlyrepresent 3 to 8 methylene groups which together with the alkylidenecarbon complete a ring, the ring optionally containing 1 to 2 doublebonds and the ring being optionally substituted with 1 or 2 R₂ groups;

compounds of Formula 4

wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkyl of 1 to6 carbons, and n is an integer between 0 and 2;

Z is

—N═N—,

—N(O)═N—,

—N═N(O)—,

—N═CR₁—,

—CR₁═N,

—(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

—CO—NR₁—,

—CS—NR₁—,

—NR₁—CO,

—NR₁—CS,

—COO—,

—OCO—;

—CSO—;

—OCS—;

—CO—CR₁═CR₁—;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,or alkylthio of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

Y is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y represents adirect valence bond between said (CR₂═CR₂)_(n′) group and B;

A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons, and

Z₂ is OR₁ or OR₁₈ where R₁₈ is is phenyl, benzyl, lower alkyl or loweralkoxy substituted phenyl, or Z₂ is OSi(R₂)₃, OCOR₁₄, OC(R₁₅)(R₁₆)X₂R₁₇,N(R₁₄)₂, NHCON(R₁₄)₂, NHCSN(R₁₄)₂, where X₂ is O or S; R₁₄ is hydrogen,alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl,C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀alkyl,naphthyl-C₁-C₁₀alkyl; R₁₅ and R₁₆ are hydrogen or lower alkyl of 1 to 6carbons, R₁₇ is lower alkyl of 1 to 6 carbons, or R₁₆ and R₁₇ jointlyform a ring having a total of 4 to 5 carbons and the X₂ heteroatom;

compounds of Formula 5

wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkyl of 1 to6 carbons, and n is an integer between 0 and 2;

Z is

—N═N—,

—N(O)═N—,

—N═N(O)—,

—N═CR₁—,

—CR₁═N,

—(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

—CO—NR₁—,

—CS—NR₁—,

—NR₁—CO,

—NR₁—CS,

—COO—,

—OCO—;

—CSO—;

—OCS—;

—CO—CR₁═CR₁—;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,or alkylthio of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

Y is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y represents adirect valence bond between said (CR₂═CR₂)_(n′) group and B;

A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons;

X₂ is O, S, SO or SO₂, and

R₂₀ is Si(C₁₋₆alkyl)₃, R₁₄, COR₁₄, SO₂R₂₁, where R₁₄ is hydrogen, alkylof 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 doublebond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl,C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀alkyl,napthyl-C₁-C₁₀alkyl, or R₂₀ is hydroxyalkyl, aminoalkyl or thioalkylhaving 1 to 10 carbons; and R₂₁ is alkyl of 1 to 10 carbons, fluoroalkylof 1 to 10 carbons, or carbocyclic aryl selected from the groupconsisting of phenyl, C₁-C₁₀-alkylphenyl and phenyl-C₁-C₁₀alkyl, and

compounds of Formula 6

wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkyl of 1 to6 carbons, and n is an integer between 0 and 2;

Z is

—N═N—,

—N(O)═N—,

—N═N(O)—,

—N═CR₁—,

—CR₁═N,

—(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

—CO—NR₁—,

—CS—NR₁—,

—NR₁—CO,

—NR₁—CS,

—COO—,

—OCO—;

—CSO—;

—OCS—;

—CO—CR₁═CR₁—;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,or alkylthio of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

Y is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y represents a 2direct valence bond between said (CR₂═CR₂)_(n′) group and B;

A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons;, and

R₁₄ is (R₁₅)_(r)-substituted alkyl of 1-6 carbons, (R₁₅)_(r)-substitutedalkenyl of 1-6 carbons and 1 or 2 double bonds, (R₁₅)_(r)-substitutedalkynyl of 1-6 carbons and 1 or 2 triple bonds, (R₁₅)_(r)-phenyl,(R₁₅)_(r)-naphthyl, or (R₁₅)_(r)-heteroaryl where the heteroaryl grouphas 1 to 3 heteroatoms selected from the group consisting of O, S and N,r is an integer having the values of 0-5, and

R₁₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈,NR₈CON(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈ an alkyl group having 1 to10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, analkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynylgroup having 1 to 10 carbons and 1 to 3 triple bonds, or a(trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groupsindependently have 1 to 6 carbons.

In a second aspect, this invention relates to the use of the compoundsof Formula 1 through Formula 6 for the treatment of skin-relateddiseases, including, without limitation, actinic keratoses, arsenickeratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyosesand other keratinization and hyperproliferative disorders of the skin,eczema, atopic dermatitis, Darriers disease, lichen planus, preventionand reversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The compoundsare also useful for the prevention and treatment of cancerous andprecancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thepresent compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for the compounds of the present invention include theprevention and treatment of conditions and diseases associated withHuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil^(R), diseases associated with the immune system, including useof the present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

Alternatively, those compounds of the invention which act as antagonistsof one or more retinoid receptor subtypes are useful to prevent certainundesired side effects of retinoids which are is administered for thetreatment or prevention of certain diseases or conditions. For thispurpose the retinoid antagonist compounds of the invention may beco-administered with retinoids. The compounds of the present inventionare also useful in the treatment of acute or chronic toxicity resultingfrom overdose or poisoning by retinoid drugs or Vitamin A.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 1 through Formula 6 in admixture with apharmaceutically acceptable excipient, said formulation being adaptedfor administration to a mammal, including a human being, to treat oralleviate the conditions which were described above as treatable byretinoids, to be co-administered with retinoids to eliminate or reduceside effects of retinoids, or to treat retinoid or Vitamin A overdose orpoisoning.

Biological Activity, Modes of Administration

Assay of Retinoid-Like or Retinoid Antagonist-Like Biological Activity

A classic measure of retinoic acid activity involves measuring theeffects of retinoic acid on ornithine decarboxylase. The original workon the correlation between retinoic acid and decrease in cellproliferation was done by Verma & Boutwell, Cancer Research, 1977, 37,2196-2201. That reference discloses that ornithine decarboxylase (ODC)activity increased precedent to polyamine biosynthesis. It has beenestablished elsewhere that increases in polyamine synthesis can becorrelated or associated with cellular proliferation. Thus, if ODCactivity could be inhibited, cell hyperproliferation could be modulated.Although all cases for ODC activity increases are unknown, it is knownthat 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. An assayessentially following the procedure set out in Cancer Research:1662-1670, 1975 may be used to demonstrate inhibition of TPA inductionof ODC by compounds of this invention. Activity of exemplary compoundsof the present invention in the above-described ODC assay is disclosedin Table 1 which provides the IC₆₀ concentration for the respectiveexemplary compound. (“IC₆₀” is that concentration of the test compoundwhich causes 60% inhibition in the ODC assay. By analogy, “IC₈₀, forexample, is that concentration of the test compound which causes 80%inhibition in the ODC assay.)

TABLE 1 ODC Assay Compound No. IC₆₀(nmols) A5 10.3 D3 8.4 C22b 10 E248.3 A16 4.3 (IC₈₀) C14 4 E79 5.3 D34 4.3 (IC₈₀) C15 14.5 E15 24.7 A270.7 E16 88.4 A23 43.7 A2 27 E72b 18 E56a 3.1 D6 1.9

Other assays described below, measure the ability of the compounds ofthe present invention to bind to, and/or activate various retinoidreceptor subtypes. When in these assays a compound binds to a givenreceptor subtype and activates the transcription of a reporter genethrough that subtype, then the compound is considered an agonist of thatreceptor subtype. Conversely, a compound is considered an antagonist ofa given receptor subtype if in the below described co-tranfection assaysthe compound does not cause significant transcriptional activation ofthe receptor regulated reporter gene, but nevertheless binds to thereceptor with a K_(d) value of less than approximately 1 micromolar. Inthe below described assays the ability of the compounds to bind toRAR_(α), RAR_(β), RAR_(γ), RXR_(α), RXR_(β) and RXR_(Γ) receptors, andthe ability or inability of the compounds to activate transcription of areporter gene through these receptor subtypes can be tested.

Specifically, a chimeric receptor transactivation assay which tests foragonist-like activity in the RAR_(α), RAR_(β), RAR_(γ), RXR_(α) receptorsubtypes, and which is based on work published by Feigner P. L. and HolmM. (1989) Focus, 11 2 is described in detail in U.S. Pat. No. 5,455,265the specification of which is hereby expressly incorporated byreference.

A holoreceptor transactivation assay and a ligand binding assay whichmeasure the antagonist/agonist like activity of the compounds of theinvention, or their ability to bind to the several retinoid receptorsubtypes, respectively, are described in published PCT Application No.WO WO93/11755 (particularly on pages 30-33 and 37-41) published on Jun.24, 1993, the specification of which is also incorporated herein byreference. A description of the holoreceptor transactivation assay isalso provided below.

Holoreceptor Transactivation Assay

CV1 cells (5,000 cells/well) were transfected with an RAR reporterplasmid MTV-TREp-LUC (50 ng) along with one of the RAR expressionvectors (10 ng) in an automated 96-well format by the calcium phosphateprocedure of Heyman et al. Cell 68, 397-406, (1992). For RXR_(α) andRXR_(γ) transactivation assays, an RXR-responsive reporter plasmidCRBPII-tk-LUC (50 ng) along with the appropriate RXR expression vectors(10 ng) was used substantially as described by Heyman et al. above, andAllegretto et al. J. Biol. Chem. 268, 26625-26633. For RXR_(β)transactivation assays, an RXR-responsive reporter plasmid CPRE-tk-LUC(50 mg) along with RXR_(β) expression vector (10 mg) was used asdescribed in above. These reporters contain DRI elements from humanCRBPII and certain DRI elements from promoter, respectively. (seeMangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp319-349, Raven Press Ltd., New York and Heyman et al., cited above) (1,8). A β-galactosidase (50 ng) expression vector was used as an internalcontrol in the transfections to normalize for variations in transfectionefficiency. The cells were transfected in triplicate for 6 hours,followed by incubation with retinoids for 36 hours, and the extractswere assayed for luciferase and β-galactosidase activities. The detailedexperimental procedure for holoreceptor transactivations has beendescribed in Heyman et al. above, and Allegretto et al. cited above. Theresults obtained in this assay are expressed in EC₅₀ numbers, as theyare also in the chimeric receptor transactivation assay. The Heyman etal. Cell 68, 397-406, Allegretto et al. J. Biol. Chem. 268, 26625-26633,and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine,pp 319-349, Raven Press Ltd., New York, are expressly incorporatedherein by reference. The results of ligand binding assay are expressedin K_(d) numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp3099-3108, expressly incorporated herein by reference.)

Table 2 shows the results of the ligand binding assay for certainexemplary compounds of the invention for the receptor subtypes in theRAR group.

TABLE 2 Ligand Binding Assay Compound K_(d) (nanomolar, nM) No. RARαRARβ RARγ A6 125 36 127 D4 1000 132 363 C25 19 12 42 E27 551 535 >1000A18 538 193 162 E80 394 531 901 D34 235 200 530 E14 36 35 455 A28 4 3 42E17 192 378 >1000 A24 283 92 259 A2a 150 219 421 E67 77 302 375 D7 >1000226 >1000

Modes of Administration

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, by Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form. If the drug is to be administeredsystemically, it may be confected as a powder, pill, tablet or the likeor as a syrup or elixir suitable for oral administration. Forintravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards it expansion. In certain instances, the compoundpotentially may be used in prophylactic manner to prevent onset of aparticular condition.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per milliliter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg per day of body weight would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

Those partial or pan retinoid antagonist compounds of the invention,when used to take advantage of their antagonist property, can beco-administered to mammals, including humans, with retinoid agonistsand, by means of pharmacological selectivity or site-specific delivery,preferentially prevent the undesired effects of certain retinoidagonists. The antagonist compounds of the invention can also be used totreat Vitamin A overdose, acute or chronic, resulting either from theexcessive intake of vitamin A supplements or from the ingestion of liverof certain fish and animals that contain high levels of Vitamin A. Stillfurther, the antagonist compounds of the invention can also be used totreat acute or chronic toxicity caused by retinoid drugs. It has beenknown in the art that the toxicities observed with hypervitaminosis Asyndrome (headache, skin peeling, bone toxicity, dyslipidemias) aresimilar or identical with toxicities observed with other retinoids,suggesting a common biological cause, that is RAR activation. Becausethe antagonist compounds of the present invention block RAR activation,they are suitable for treating the foregoing toxicities.

Generally speaking, for therapeutic applications in mammals, theantagonist compounds of the invention can be admistered enterally ortopically as an antidote to vitamin A, or antidote to retinoid toxicityresulting from overdose or prolonged exposure, after intake of thecausative factor (vitamin A, vitamin A precursor, or other retinoid) hasbeen discontinued. Alternatively, the antagonist compounds of theinvention are co-administered with retinoid drugs, in situations wherethe retinoid provides a therapeutic benefit, and where theco-administered antagonist compound alleviates or eliminates one or moreundesired side effects of the retinoid. For this type of application theantagonist compound may be administered in a site-specific manner, forexample as a topically applied cream or lotion while the co-administeredretinoid may be given enterally. For therapeutic applications theantagonist compounds of the invention, like the retinoid agonistscompounds, are incorporated into pharmaceutical is compositions, such astablets, pills, capsules, solutions, suspensions, creams, ointments,gels, salves, lotions and the like, using such pharmaceuticallyacceptable excipients and vehicles which per se are well known in theart. For topical application, the antagonist compounds of the inventioncould also be administered as a powder or spray, particularly in aerosolform. If the drug is to be administered systemically, it may beconfected as a powder, pill, tablet or the like or as a syrup or elixirsuitable for oral administration. For intravenous or intraperitonealadministration, the compound will be prepared as a solution orsuspension capable of being administered by injection. In certain cases,it may be useful to formulate these compounds by injection. In certaincases, it may be useful to formulate these compounds in suppository formor as extended release formulation for deposit under the skin orintramuscular injection.

The antagonist compounds also, like the retinoid agonists of theinvention, will be administered in a therapeutically effective dose. Atherapeutic concentration will be that concentration which effectsreduction of the particular condition, or retards its expansion. Whenco-administering the compounds of the invention to blockretinoid-induced toxicity or side effects, the antagonist compounds ofthe invention are used in a prophylactic manner to prevent onset of aparticular condition, such as skin irritation.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the chronic or acute retinoid toxicity or related condition beingtreated. Such concentrations can be arrived at through routineexperimentation. However, it is anticipated that a formulationcontaining between 0.01 and 1.0 milligrams per mililiter of formulationwill constitute a therapeutically effective concentration for totalapplication. If administered systemically, an amount between 0.01 and 5mg per kg per day of body weight would be expected to effect atherapeutic result.

General Embodiments and Synthetic Methodology

Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenylrefers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Similarly,the term alkynyl refers to and covers normal alkynyl, and branch chainalkynyl groups having one or more triple bonds.

Lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and as applicable 3to 6 carbons for lower branch chained and cycloalkyl groups. Loweralkenyl is defined similarly having 2 to 6 carbons for normal loweralkenyl groups, and 3 to 6 carbons for branch chained and cyclo-loweralkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6carbons for normal lower alkynyl groups, and 4 to 6 carbons for branchchained lower alkynyl groups.

The term “ester” as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. It includes organic and inorganic esters. Where B (of Formula1 through 6) is —COOH, this term covers the products derived fromtreatment of this function with alcohols or thiols preferably withaliphatic alcohols having 1-6 carbons. Where the ester is derived fromcompounds where B is —CH₂OH, this term covers compounds derived fromorganic acids capable of forming esters including phosphorous based andsulfur based acids, or compounds of the formula —CH₂OCOR₁₁ where R₁₁ isany substituted or unsubstituted aliphatic, aromatic, heteroaromatic oraliphatic aromatic group, preferably with 1-6 carbons in the aliphaticportions.

Unless stated otherwise in this application, preferred esters arederived from the saturated aliphatic alcohols or acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic alcohols andacids of 5 to 10 carbon atoms. Particularly preferred aliphatic estersare those derived from lower alkyl acids and alcohols. Also preferredare the phenyl or lower alkyl phenyl esters.

Amides has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Unless statedotherwise in this application, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms. Particularly preferred amides arethose derived from substituted and unsubstituted lower alkyl amines.Also preferred are mono- and disubstituted amides derived from thesubstituted and unsubstituted phenyl or lower alkylphenyl amines.Unsubstituted amides are also preferred.

Acetals and ketals include the radicals of the formula-CK where K is(—OR)₂. Here, R is lower alkyl. Also, K may be —OR₇O— where R₇ is loweralkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compounds inthis invention having a functionality capable of forming a salt, forexample an acid functionality. A pharmaceutically acceptable salt is anysalt which retains the activity of the parent compound and does notimpart any deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri-acid may also be used.

Some of the compounds of the present invention may have trans and cis (Eand Z) isomers. In addition, the compounds of the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. Still further oxime and relatedcompounds of the present invention may exist in syn and anti isomericforms. The scope of the present invention is intended to cover all suchisomers per se, as well as mixtures of cis and trans isomers, mixturesof syn and anti isomers, mixtures of diastereomers and racemic mixturesof enantiomers (optical isomers) as well. In the present applicationwhen no specific mention is made of the configuration (cis, trans, synor anti or R or S) of a compound (or of an asymmetric carbon) then amixture of such isomers, or either one of the isomers is intended. In asimilar vein, when in the chemical structural formulas of thisapplication a straight line representing a valence bond is drawn to anasymmetric carbon, then isomers of both R and S configuration, as wellas their mixtures are intended. Defined stereochemistry about anasymmetric carbon is indicated in the formulas (where applicable) by asolid triangle showing β configuration, or by a hashed line showing αconfiguration.

Referring now to the nomenclature used in naming the compounds of theinvention and intermediate compounds leading thereto, the system fornumbering the tetrahydronaphthalene ring is demonstrated as shown by thestructural formulas of Compounds F, G and A2. Compound A2 is anexemplary compound of the invention within the scope of Formula 2 andCompounds F and G are two exemplary intermediates utilized in thesynthesis of the compounds of the invention. The numbering systemsillustrated here corresponds substantially to IUPAC rules, and will bereadily apparent to those skilled in the art as it is applied in theensuing description.

Generally speaking, the compounds of the invention are made in syntheticsteps which involve the formation of the tetrahydronaphthalene,dihydronaphthalene, indane or suberane moiety, substituted with thedesired R₁, R₂ and R₃ groups and with a reactive group, such as bromogroup, that allows coupling with a reagent that introduces the—Z—Y(R₂)—A—B group. Such a reagent can be generally described asX₃—Z—Y(R₂)—A—B where X₃ is a reactive group, in many instances a leavinggroup, such as halogen. The —Z—Y(R₂)—A—B group may also be formed in aseries of reactions performed starting with the tetrahydronaphthalene,dihydronaphthalene, indane or suberane molecule that has the appropriatereactive group or reactive position. in the aromatic nucleus.

The substituent or substituents in the 5 or 8 positions of thetetrahydronaphthalene or dihydronaphthalene (and by analogy in thecorresponding positions of indane and suberan) which are designated asR₄ and X₂R₅ in Formula 1, as (X₂R₁₈)₂ in Formula 2, ═C(R₁₉)₂ in Formula3, N═Z₂ in Formula 4, X₂R₂₀ in Formula 5 and R₁₄ in Formula 6 may beintroduced into the tetrahydronaphthalene or dihydronaphthalene ringmoiety before coupling with the reagent X₃—Z—Y(R₂)—A—B, or beforeformation of the —Z—Y(R₂)—A—B group. In other examples coupling with thereagent X₃—Z—Y(R₂)—A—B or formation of the —Z—Y(R₂)—A—B group attachedto the tetrahydronaphthalene or dihydronaphthalene nucleus is performedfirst to yield an intermediate that includes the tetrahydronaphthalene,dihydronaphthalene (and by analogy indane or suberane) moiety covalentlylinked to the —Z—Y(R₂)—A—B group, but which has a reactive group,preferably such as an oxo or trifluoromethanesulfonyloxy function, inthe 5 or 8 position. In these cases the substituents of these twopositions, as defined in Formulas 1-6, are introduced into theintermediate by appropriate reactions which are described in detailbelow.

The synthetic methodology employed for the synthesis of the compounds ofthe present invention may also include transformations of the groupdesignated as —A—B in Formulas 1-6. Generally speaking thesetransformations involve reactions well within the skill of thepracticing organic chemist. In this regard the following well known andpublished general principles and synthetic methodology are brieflydescribed.

Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, “AdvancedOrganic Chemistry,” 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

To increase the value of n in the compounds of X₃—Z—Y(R₂)—A—B orprecursors thereof, before affecting the coupling or linkage with thetetrahydronaphthalene, dihydronaphthalene nucleus (where such compoundsare not available from a commercial source) aromatic or heteroaromaticcarboxylic acids are subjected to homologation by successive treatmentunder Arndt-Eistert conditions or other homologation procedures.Alternatively, derivatives which are not carboxylic acids may also behomologated by appropriate procedures. The homologated acids can then beesterified by the general procedure outlined in the preceding paragraph.

Compounds of formula X₃—Z—Y(R₂)—A—B (or of the invention as set forth inFormulas 1 through 6, as applicable) where A is an alkenyl group havingone or more double bonds can be made for example, by synthetic schemeswell known to the practicing organic chemist; for example by Wittig andlike reactions, or by introduction of a double bond by elimination ofhalogen from an alpha-halo-arylalkyl-carboxylic acid, ester or likecarboxaldehyde. Compounds of formula X₃—Z—Y(R₁₂)—A—B (or of theinvention as set forth in Formulas 1 through 6, as applicable) where theA group has a triple (acetylenic) bond can be made by reaction of acorresponding aromatic methyl ketone with strong base, such as lithiumdiisopropyl amide, reaction with diethyl chlorophosphate and subsequentaddition of lithium diisopropylamide.

The acids and salts derived from compounds of the invention are readilyobtainable from the corresponding esters. Basic saponification with analkali metal base will provide the acid. For example, an ester of theinvention may be dissolved in a polar solvent such as an alkanol,preferably under an inert atmosphere at room temperature, with about athree molar excess of base, for example, lithium hydroxide or potassiumhydroxide. The solution is stirred for an extended period of time,between 15 and 20 hours, cooled, acidified and the hydrolysate recoveredby conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the ester is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about −10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert organic solventsuch as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, “AdvancedOrganic Chemistry”, 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alkyl halides underWilliamson reaction conditions (March, Ibid, pg. 357) gives thecorresponding ethers. These alcohols can be converted to esters byreacting them with appropriate acids in the presence of acid catalystsor dicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron. 1978. 34. 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Reagents of formula X₃—Z—Y(R₂)—A—B (or compounds of the invention as setforth in Formulas 1 through 6, as applicable) where B is H can beprepared from the corresponding halogenated aromatic or heteroaromaticcompounds, preferably where the halogen is I.

Specific Embodiments

With reference to the symbol Y in Formulas 1 through 6, the preferredcompounds of the invention are those where Y is phenyl, naphthyl,pyridyl, thienyl or furyl. Even more preferred are compounds where Y isphenyl, naphthyl or pyridyl. As far as substitutions on the Y (phenyl),Y (pyridyl) and M) naphthyl groups are concerned, compounds arepreferred where the phenyl group is 1,4 (para) substituted, the naphthylgroup is 2,6 substituted and where the pyridine ring is 2,5 substituted.(Substitution in the 2,5 positions in the “pyridine” nomenclaturecorresponds to substitution in the 6-position in the “nicotinic acid”nomenclature.) In the preferred compounds of the invention there is nooptional R₂ substituent on the Y group.

The A—B group of the preferred compounds is (CH₂)_(n)—COOH or(CH₂)_(n)—COOR₈, where R₈ is defined as above. Even more preferably n iszero and R₈ is lower alkyl.

Referring still to the preferred compounds of Formulas 1 through 6, theX₁ group is preferably C(R₁)₂, that is the preferred compounds aretetrahydronaphthalene or dihydronaphthalene derivatives. The aromaticportion of the tetrahydronaphthalene or dihydronaphthalene moiety ispreferably substituted only by the —Z—Y(R₂)—A—B group. In other words,in the preferred compounds there is no R₂ substituent (other thanhydrogen). Similarly, in the preferred compounds of the invention thereis no R₃ substituent (other than hydrogen). The R₁ substituent of thecompounds of the invention is preferably lower alkyl, and even morepreferably methyl.

Preferred Z groups are:

—(CR₁═CR₁)_(n′)— where n′ is 0, 1, or 3 (when n′ is 3 then Y representsa direct valence bond between the —(CR₁═CR₁)_(n), — group and the —A—Bgroup),

—N═N—,

—CO—CR₁═CR₁—,

—COO—, and

—CONH—.

Referring now specifically to compounds in accordance with Formula 1,compounds in these series are preferred where X₂ is O, the R₄ group isH, lower alkyl, or CH₂COOR₈, and R₅ is H, Si(C₁₋₆alkyl)₃, COR₁₄,C(R₁₅)(R₁₆)X₂R₁₇. COCH₃ for COR₁₄, and CH₂OCH₃ and2-(1-tetrahydropyranyl) for the C(R₁₅)(R₁₆)X₂R₁₇ group are particularlypreferred.

The most preferred compounds in accordance with Formula 1 are listedbelow in the Table for Formula 1A and with reference to that formula.

Formula 1A TABLE For Formula 1A Configuration, When Applicable Compoundand or position No. R₄ R₅ Z Y R₈ of substituent Z A-32 CH₂COOEt H CH═CH1,4-C₆H₄—¹ Et 2 B-3 H t-butyl — 2,6-C₁₀H₆ ² Et 2 dimethyl silyl B-4 H H— 2,6-C₁₀H₆ ² Et 2 B-5 H H — 2,6-C₁₀—H₆ ² H 2 B-8 H CH₂OCH₃ — 2,6-C₁₀H₆² Et 2 B-9 H CH₂OCH₃ — 2,6-C₁₀H₆ ² H 2 B-10 H COCH₃ — 2,6-C₁₀H₆ Et 2C-13 H H polyene⁴ — Et 2 C-19 H H polyene⁴ — H 2 C-26 H CH₂OCH₃ polyene⁴— Et 2 C-27 H CH₂OCH₃ polyene⁴ — H 2 C-29 H THP³ polyene⁴ — Et 2 C-31 HTHP³ polyene⁴ — H 2 D-1 CH₂COOEt H —N═N— 1,4-C₆H₄ ¹ Et 2 D-5 H H —N═N—1,4-C₆H₄ ¹ Et 2 D-6 H CH₂OCH₃ —N═N— 1,5-C₆H₄ ¹ Et 2 D-7 H CH₂OCH₃ —N═N1,4-C₆H₄ ¹ H 2 D-27 H CH₂OCH₃ CO—CH═CH— 1,4-C₆H₄ ¹ H 3 E-32 H H CO—NH1,4-C₆H₄ ¹ Et 2 E-33 H H —CO—NH— 1,4-C₆H₄ ¹ H 2 E-34 H CH₂OCH₃ —CO—NH—1,4-C₆H₄ ¹ Et 2 E-35 H CH₂OCH₃ —CO—NH 1,4-C₆H₄ ¹ H 2 E-37 H H —CO—O—1,4-C₆H₄ ¹ (CH₂)₂Si(CH₃)₃ 2 E-38 H CH₂OCH₃ —CO—O— 1,4-C₆H₄ ¹(CH₂)₂Si(CH₃)₃ 2 E-39 H CH₂OCH₃ —CO—O— 1,4-C₆H₄ ¹ H 2 E-40 H H —CO—O—1,4-C₆H₄ ¹ Et 2 E-41 H CH₂OCH₃ —CO—O— 1,4-C₆H₄ ¹ Et 2 E-49 CH₂COOEtCOCH₃ —CO—NH— 1,4-C₆H₄ ¹ Et 2 E-54 CH₂COOEt H —CO—O— 1,4-C₆H₄ ¹ Et 2E-56 H THP³ —CO—O— 1,4-C₆H₄ ¹ Et 2 E-60 H THP³ —CO—O— 1,4-C₆H₄ ¹ Benzyl2 E-64 H THP³ —CO—O— 1,4-C₆H₄ ¹ H 2 E-65 H THP³ —CO—O— 1,4-C₆H₄ ¹ H 2E-66 H THP³ —CO—O— 1,4-C₆H₄ ¹ H 2 E-67 H THP³ —CO—O— 1,4-C₆H₄ ¹ H 2 E-70H THP³ —CO—NH 1,4-C₆H₄ ¹ Et 2 E-72 H THP³ —CO—NH— 1,4-C₆H₄ ¹ Et 2 E-74 HTHP³ —CO—NH 1,4-C₆H₄ ¹ H 2 E-75 H THP³ —CO—NH 1,4-C₆H₄ ¹ H 2 E-76 H THP³—CO—NH 1,4-C₆H₄ ¹ H 2 E-77 H THP³ —CO—NH 1,4-C₆H₄ ¹ H 2 E-82 H H —CO—O—1,4-C₆H₄ ¹ Benzyl 2 ¹1,4-C₆H₄ stands for 1,4-substituted phenyl²2,6-C₁₀H₆ stands for 2,6-substituted naphthalene ³THP stands for2-(1-tetrahydropyranyl). ⁴polyene stands for —C(CH₃)═CH—CH═CH—(CH₃)═CH—

Referring now to compounds in accordance with Formula 2, compounds inthese series are preferred where the two X₂R₁₈ jointly symbolize an oxo(═O) group, or where the two X₂R₁₈ groups each symbolize an S-alkylgroup, or where where the two X₂R₁₈ groups jointly symbolize two sulphuratoms connected with a alkyledene bridge as in a cyclic thioketalfunction.

The most preferred compounds in accordance with Formula 2 are listedbelow in the Table for Formula 2A and with reference to that formula.

Formula 2A TABLE FOR FORMULA 2A Compound No. X₂ R₁₈ Z Y R₈ A-2 O¹ ——CH═CH— 1,4-C₆H₄ ² Et A-2a O¹ — —CH═CH— 1,4-C₆H₄ ² H A-23 S (CH₂)₃ ³——CH═CH— 1,4-C₆H₄ ² Et A-24 S (CH₂)₃ ³— —CH═CH— 1,4-C₆H₄ ² H B-1 — H⁴ —2,6-C₁₀H₆ ⁵ Et B-2 — H⁴ — 2,6-C₁₀H₆ ⁵ H B-6 O¹ — — 2,6-C₁₀H₆ ⁵ Et B-7 O¹— — 2,6-C₁₀H₆ ⁵ H C-5 O¹ — polyene⁶ — Et D-10 O¹ — —N═N— 1,4-C₆H₄ ² EtE-28 O¹ — —CO—NH— 1,4-C₆H₄ ² Et E-29 O¹ — —CO—NH— 1,4-C₆H₄ ² H E-36 O¹ ——COO— 1,4-C₆H₂ ² (CH₂)₂Si(CH₃)₃ E-44 O¹ — —COO— 1,4-C₆H₄ ² Et E-81 O¹ ——COO— 1,4-C₆H₄ ² benzyl ¹The two X₂—R₁₈ jointly symbolize and oxo (═O)group; ²1,4-C₆H₄ stands for 1,4-substituted phenyl; ³The three methylenegroups form a propylene bridge; ⁴Each of the two X₂R₁₈ groups is H;⁵2,5-C₁₀H₆ stands for 2,6-substituted naphthalene. ⁶polyene stands for—C(CH₃)═CH—CH═CH—(CH₃)═CH—

Compounds in accordance with Formula 3 are preferred where the R₁₉,groups are alkyl, especially lower alkyl, most preferably methyl orethyl, where the two R₁₉ groups together with the methyledene carbonform a 5 or 6 membered ring, and where the R₁₉ groups are phenyl.Compounds are also preferred in accordance with this formula where oneof the R₁₉ groups is COOR₈, or COOH, and the other is H.

The most preferred compounds in accordance with Formula 3 are listedbelow in the Table for Formula 3A and with reference to that formula.

Formula 3A TABLE FOR FORMULA 3A Configuration when applicable Compoundand/or position No. R₁₉′ R₁₉″ Z Y R₈ of substituent A-25 CH₃ CH₃ —CH═CH—1,4-C₆H₄ ¹ Et 2 A-26 CH₃ CH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2 A-27 CH₂CH₃ CH₂CH₃—CH═CH— 1,4-C₆H₄ ¹ Et 2 A-28 CH₂CH₃ CH₂CH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2 A-29(CH₂)₅ ² — —CH═CH— 1,4-C₆H₄ ¹ Et 2 A-31 (CH₂)₅ ² — —CH═CH— 1,4-C₆H₄ ¹ H2 C-17a COOEt H polyene³ — Et 2, anti C-17b COOEt H polyene³ — Et 2, synC-36 CH₃ CH₃ polyene³ — Et 2 C-41 phenyl phenyl polyene³ — Et 2 D-2aCOOEt H —N═N— 1,4-C₆H₄ ¹ Et 2 D-23 CH₃ CH₃ —CO—CH═CH— 1,4-C₆H₄ ¹ H 3E-13 CH₃ CH₃ —COO— 1,4-C₅H₄ ¹ CH₂CH₂SiMe₃ 2 E-14 CH₃ CH₃ —COO— 1,4-C₆H₄¹ H 2 E-15 CH₃ CH₃ —COO— 1,4-C₆H₄ ¹ Et 2 E-16 CH₃ CH₃ —CONH— 1,4-C₆H₄ ¹Et 2 E-17 CH₃ CH₃ —CONH— 1,4-C₆H₄ ¹ H 2 E-50a COOEt H —CONH— 1,4-C₆H₄ ¹Et 2 E-52 COOH H —CONH— 1,4-C₆H₄ ¹ H 2, cis E-53 COOH H —CONH— 1,4-C₆H₄¹ H 2, trans ¹1,4-C₆H₄ stands for 1,4-substituted phenyl ²The5-methylene groups together with the methyledene group form a 6-memberedring. ³polyene stands for C(CH₃)═CH—CH═CH—C(CH₃)═CH—

Referring now to compounds in accordance with Formula 4, compounds inthese series are preferred where the Z₂ group is O-lower alkyl,especially OCH₃ or OCH₂CH₃. The most preferred compounds in accordancewith Formula 4 are listed below in the Table for Formula 4A and withreference to that formula.

Formula 4A TABLE FOR FORMULA 4A Position of Z Substituent and/orCompound configuration as No. Z₂ Z Y R₈ Applicable A-3 OCH₃ —CH═CH—1,4-C₆H₄ ¹ Et 2, anti A-4 OCH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2, anti A-5 OCH₂CH₃—CH═CH— 1,4-C₆H₄ ¹ Et 2, anti A-6 OCH₃CH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2, antiA-7 OH —CH═CH— 1,4-C₆H₄ ¹ Et 2, anti A-8 OH —CH═CH— 1,4-C₆H₄ ¹ H 2, antiB-11 OCH₃ — 2,6-C₁₀H₆ ² Et 2, anti B-12 OCH₃ — 2,6-C₁₀H₆ ² H 2, anti C-6OCH₃ polyene³ — Et 2, anti C-22a OCH₃CH₃ polyene³ — Et 2, syn C-22bOCH₂CH₃ polyene³ — Et 2, anti C-24 OCH₂CH₃ polyene³ — H 2, syn C-25OCH₂CH₃ polyene³ — H 2, anti D-3 OCH₃ —N═N— 1,4-C₆H₄ ¹ Et 2, anti D-4OCH₃ —N═N— 1,4-C₆H₄ ¹ H 2, anti D-29 OCH₃ —CO—CH═CH— 1,4-C₆H₄ ¹ H 3 E-30OCH₃ —CONH— 1,4-C₆H₄ ¹ Et 2, anti E-31 OCH₃ —CONH— 1,4-C₆H₄ ¹ H 2, antiE-42 OCH₃ —COO— 1,4-C₆H₄ ¹ (CH₃)SiMe₃ 2, anti E-43 OCH₃ —COO— 1,4-C₆H₄ ¹H 2, anti E-46 OCH₃ —COO— 1,4-C₆H₄ ¹ Et 2, anti ¹stands for1,4-substituted phenyl ²stands for 2,6-substituted naphthyl ³polyenestands for C(CH₃)═CH—CH═CH—C(CH₃)═CH—

Compounds in accordance with Formula 5 are preferred where the R₂₀ groupis lower alkyl, phenyl or SO₂CF₃.

The most preferred compounds in accordance with Formula 5 are listedbelow in the Table for Formula 5A and with reference to that formula.

Formula 5A TABLE FOR FORMULA 5A Compound No. X₂ R₂₀ Z Y R₈ A-9 O SO₂CF₃—CH═CH— 1,4-C₆H₄ ¹ Et A-16 S phenyl —CH═CH— 1,4-C₆H₄ ¹ Et A-18 S phenyl—CH═CH— 1,4-C₆H₄ ¹ H A-17 SO₂ phenyl —CH═CH— 1,4-C₆H₄ ¹ Et A-19 SO₂phenyl —CH═CH— 1,4-C₆H₄ ¹ H A-20 S CH₂CH₃ —CH═CH— 1,4-C₆H₄ ¹ Et A-21 SCH₂CH₃ —CH═CH— 1,4-C₆H₄ ¹ H A-22 SO₂ CH₂CH₃ —CH═CH— 1,4-C₆H₄ ¹ H C-10 Sphenyl polyene² — Et C-11 SO₂ phenyl polyene² — Et C-12 SO phenylpolyene² — Et C-14 O SO₂CF₃ polyene² — Et C-28 O trimethylsilyl polyene²— Et D-11 O SO₂CF₃ —N═N— 1,4-C₆H₄ ¹ Et E-20 S phenyl —CONH— 1,4-C₆H₄ ¹Et E-21 S phenyl —CONH— 1,4-C₆H₄ ¹ H E-22 SO₂ phenyl —CONH— 1,4-C₆H₄ ¹ HE-23 S phenyl —COO— 1,4-C₆H₄ ¹ Et E-24 SO₂ phenyl —COO— 1,4-C₆H₄ ¹ EtE-25 S phenyl —COO— 1,4-C₆H₄ ¹ (CH₂)₂Si(CH₃)₃ E-26 S phenyl —COO—1,4-C₆H₄ ¹ H E-27 SO₂ phenyl —COO— 1,4-C₆H₄ ¹ H ¹stands for1,4-substituted phenyl ²polyene stands for C(CH₃)═CH—CH═CH—(CH₃)═CH

Referring now to compounds in accordance with Formula 6, compounds inthese series are preferred where the R₁₄ group is thiazolyl, morepreferably 2-thiazolyl, thienyl, more preferably 2-thienyl, branchedchain lower alkyl, more preferably t-butyl, or where R₁₄ is CH₂COOR₈ orCH₂COOH.

The most preferred compounds in accordance with Formula 6 are listedbelow in the Table for Formula 6A and with reference to that formula.

Formula 6A TABLE FOR FORMULA 6A Compound Position of Z Sub- No. R₁₄ Z YR₈ stituent A-10 2-thiazolyl —CH═CH— 1,4-C₆H₄ ¹ Et 2 A-12 2-thiazolyl—CH═CH— 1,4-C₆H₄ ¹ H 2 A-13 2-thienyl —CH═CH— 1,4-C₆H₄ ¹ Et 2 A-152-thienyl —CH═CH— 1,4-C₆H₄ ¹ H 2 C-15 2-thienyl polyene² — Et 2 C-202-thienyl polyene² — H 2 C-46 t-butyl polyene² — Et 2 D-2b CH₂COOEt—N═N— 1,4-C₆H₄ ¹ Et 2 D-12 2-thienyl —N═N— 1,4-C₆H₄ ¹ Et 2 D-132-thienyl —N═N— 1,4-C₆H₄ ¹ H 2 D-18 CH₂COOEt CO—CH═CH— 1,4-C₆H₄ ¹ H 3D-20 t-butyl —CO—CH═CH— 1,4-C₆H₄ ¹ H 3 D-34 2-thienyl CO—CH═CH— 1,4-C₆H₄¹ H 3 E-7 2-thienyl —CO—NH— 1,4-C₆H₄ ¹ Et 2 E-8 2-thienyl —CO—NH—1,4-C₆H₄ ¹ H 2 E-9 2-thienyl —COO— 1,4-C₆H₄ ¹ Et 2 E-10 2-thienyl —COO—1,4-C₆H₄ ¹ (CH₂)₂SiMe₃ 2 E-11 2-thienyl —COO— 1,4-C₆H₄ ¹ H 2 E-50bCH₂—COOEt —CO—NH— 1,4-C₆H₄ ¹ Et 2 E-55 CH₂COOEt —COO— 1,4-C₆H₄ ¹ Et 2E-79 t-butyl —CO—NH— 1,4-C₆H₄ ¹ Et 2 E-80 t-butyl —CO—NH— 1,4-C₆H₄ ¹ H 2¹stands for 1,4-substituted phenyl ²polyene stands forC(CH₃)═CH—CH═CH—C(CH₃)═CH—

The compounds of this invention can be made by the general proceduresoutlined above under the title ““GENERAL EMBODIMENTS AND SYNTHETICMETHODOLOGY”. The following chemical pathways represent the presentlycontemplated best synthetic routes to certain exemplary compounds of theinvention illustrated here. However, the synthetic chemist will readilyappreciate that the conditions set out here for these specificembodiments can be generalized to any and all of the compoundsrepresented by Formulas 1 through 6.

Important starting materials for the synthesis of the preferredcompounds of the invention are6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F),7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and theisomeric bromo compound,6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H).Compound G can be obtained as described in J. Med. Chem. 1995, 38,4764-4767, and as shown in Reaction Scheme 1. Thus, referring nowspecifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (CompoundB, made by esterification of 3-bromophenylacetic acid) is reduced withdiisobutylaluminum hydride (DIBAL H) to yield(3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in aWittig reaction with (carbethoxymethylene)triphenylphosphorane toprovide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. Thelatter compounds are hydrogenated to yield ethyl4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with theGrignard reagent derived from methylbromide to give the tertiary alcohol5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should beapparent to those skilled in the art, that the choice of the Grignardreagent used in this reaction step determines the nature of the R₁substituent in the resulting compounds of the invention.) Compound E isthen treated with acid to cyclize it and to form6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F).Compound F is oxidized with chromium trioxide to yield7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Theisomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound H) can be obtained, starting with ethyl(4-bromophenyl)acetate, in accordance with the sequence of reactionsillustrated in Reaction Scheme 1 for Compound G.

6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) canalso be obtained in accordance with the published literature procedure:Mathur et al. Tetrahedron, 41, 1509-1516 (1985).

Another important starting material for the synthesis of severalpreferred compounds of the invention is3,4-dihydro-4,4-dimethyl-7-aminonaphthalen-1(2H)-one (Compound D9) whichis prepared from the known 3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one,by nitration and subsequent catalytic reduction of the intermediate3,4-dihydro-4,4-dimethyl-7-nitronaphthalen-1(2H)-one (Compound D8), asis described in the enclosed description of specific examples.

Still other important starting materials for the synthesis of severalpreferred compounds of the invention are the isomeric3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (Compound D14a);and 3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (CompoundD14b). These are prepared by reacting1,2,3,4-tetrahydro-1,1-dimethylnaphthalene with acetyl chloride in aFriedel-Crafts type reaction, followed by oxidation with chromiumtrioxide of the isomeric acetyl derivatives. These compounds can also beobtained by an alternative procedure from Compounds G and Hrespectively. The experimental conditions of these preparations aredisclosed in the description of the specific examples.

Yet another important starting material for the synthesis of severalpreferred compounds of the invention is methyl5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (CompoundE2) which can be made by reaction of7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) with CO₂in the presence of t-butyl lithium, but is more advantageously preparedin the presence of palladium(II)-bis(triphenylphosphine)chloride and1,3-bis(diphenylphosphino)propane catalysts by reaction withcarbonmonoxide and methanol, as is described in the specific examples.

Referring now to Reaction Scheme 2 the synthesis of preferred examplesof compounds of the invention are described, where the Z group, withreference to Formulas 1-6 is —CH═CH—. Compounds of this type of theinvention are advantageously obtained in a direct coupling reactionbetween an ethenyl compound such as ethyl 4-vinylbenzoate, and a 6- or7-bromonaphthalene-1(2H)-one derivative, such as Compound G or CompoundH in a reaction commonly known as the Heck reaction. Reaction Scheme 2exemplifies this reaction with7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) as thestarting material. A general formula for the ethenyl compounds which aresuitable as reagents in the Heck reaction to provide these type ofcompounds of the invention is CH₂═CH₂—Y(R₂)—A—B where the symbols havethe same meaning as defined in connection with Formulas 1-6. Thesecompounds are readily available in accordance with the chemicalliterature, or otherwise in accordance with state-of-the-art. The Heckreaction is well known in the art, and is usually conducted in a basicsolvent, such as triethylamine, in the presence of a phosphine catalyst(such as tris(2-methylphenyl)phosphine or tri-O-tolylphosphine) in thepresence of palladium(II)acetate catalyst.

Those skilled in the art will readily understand that the compounds ofthe invention which have an ethylene (—CH═CH—) or substituted ethylene(—CR₁═CR₁—) linking group can also be made by a Wittig or like (HornerEmmons) reactions, which are per se well known in the art. Those skilledin the art will also readily understand that the reaction sequence shownin Reaction Scheme 2 can be readily adapted for compounds where thetetrahydronaphthalene (or other rings within the scopes of Formulas 1-6)have R₁, R₂ and R₃ substituents other than specifically shown in thisreaction scheme.

Thus in the example shown in Reaction Scheme 27-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) isreacted with ethyl 4-vinylbenzoate to yield ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethylnaphthalen-8(7H-one-2-yl)ethenyl]-benzoate(Compound A2). Ethyl 4-vinylbenzoate is available in accordance with thechemical literature, Can. J. Chem (1973) 51, 897-914, which is expresslyincorporated herein by reference. Compound A2 is an example for thecompounds of the present invention within the scope of Formula 2.Compound A2 is reacted with methoxylamine hydrochloride in an alcoholicsolvent (such as ethanol) in the presence of sodium acetate to yield themethyl oxime, ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3). Compound A3 canbe saponified by treatment with base, such as LiOH, to provide the freecarboxylic acid,(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4). Compounds A3and A4 are compounds of the invention within the sope of Formula 4. Theconditions for the saponification of Compound A3 to provide Compounds A4serve as example for several saponification reactions which yieldseveral compounds of the invention where the B group of Formulas 1-6 isa free carboxylic acid (COOH), or salt thereof.

Instead of methoxylamine hydrochloride, hydroxylamine hydrochloride, orethoxylamine hydrochloride or other analogous reagents can be used toobtain the oximes or other O-alkyl, O-aryl analogs of Compounds A3 andA4, within the scope of Formula 4. Generally speaking and with referenceto Formula 4, the oxo compounds, such as Compound A2 are reacted with areagent of the formula NH₂—Z₂, where Z₂ is defined as in connection withFormula 4. Thus, the oxo compounds analogous to Compound A2 are reactedwith a reagent of the formula H₂N—Z₂ to yield compounds of Formula 4. Asis known, when the reagent H₂N—Z₂ is NH₂OH or its salt, then thereaction is the formation of an oxime. Generally speaking the oximes arereadily formed by reacting the oxo compounds with hydroxylaminehydrochloride in a polar solvent, such as a lower alkanol, in thepresence of a buffering agent, such as sodium acetate. The reaction canbe conducted under similar conditions with a reagent of the formulaNH₂OR₁ or its salt (such as methoxylamine hydrochloride or ethoxylaminehydrochloride as demonstrated in Reaction Scheme 2) to yield compoundsof Formula 4 where Z₁ is OR₁ (R₁ is defined as in connection withFormula 4). When the reagent H₂N—Z₂ is a primary amine then the reactionis the formation of an imine. The latter reaction is usually conductedin a polar (alcoholic) solvent. Further reagents, in accordance with thegeneral formula H₂NZ₂ are those where Z₂ is NHCON(R₁₄)₂ (formation ofsemicarbazone), NHCSN(R₁₄)₂ (formation of thiosemicarbazone) and N(R₁₄)₂(formation of a hydrazone). (The symbol R₁₄ is defined as in connectionwith Formula 4.) The semicarbazones, thiosemicarbazones and hydrazonescorresponding to Formula 4 can be prepared under conditions which arewell known in the art for the formation of such derivatives of ketonecompounds. Usually these conditions are similar to the conditionsleading to the oximes described above. Typically, the hydrochloride saltof the reagent (semicarbazide, thiosemicarbazide or hydrazide) isreacted with the oxo compound such as Compound A2 in an alcoholicsolvent, in the presence of sodium acetate.

Referring now again specifically to Reaction Scheme 2, ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethylnaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) is reacted with sodium bis(trimethylsilyl) amide and2-[N,N-bis(trifuoromethane-sulfonyl)amino]-5-chloropyridine in an inertether type solvent, such as tetrahydrofuran, at low temperatures (−78°C. and 0° C.). This provides first a sodium salt intermediate which isnot isolated and not shown in the reaction scheme. The reactionsultimately result in the trifluoromethylsulfonyloxy derivative ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-naphthalen-2-yl)ethenyl]-benzoate(Compound A9). Compound A9 is within the scope of Formula 5 of thepresent invention and is also an important intermediate for thesynthesis of several compounds of the invention within the scope ofFormula 6. Compound A9 is a trifluoromethylsulfonate derivative, whichsometimes also called a “triflate” in the trade, and the CF₃SO₂ group issometimes abbreviated as “Tf” in the reaction schemes.

As is shown further in Reaction Scheme 2 for the specific examples ofthiazole and thiophene, respectively yielding Compounds A10 and A13, thetriflate derivative Compound A9 is reacted with an organometalderivative derived from the compound R₁₄H, such that the formula of theorganometal derivative is R₁₄Met (Met stands for monovalent metal),preferably R₁₄Li. (R₁₄ is defined as in connection with Formula 6.) Thereaction with the organometal derivative, preferably lithium derivativeof the formula R₁₄Li is usually conducted in an inert ether type solvent(such as tetrahydrofuran) in the presence of zinc chloride (ZnCl₂) andtetrakis(triphenylphosphine)palladium(O) (Pd(PPh₃)₄). The organolithiumreagent R₁₄Li, if not commercially available, can be prepared from thecompound R₁₄H (or its halogen derivative R₁₄-X₁ where X₁ is halogen) inan ether type solvent in accordance with known practice in the art. Thetemperature range for the reaction between the reagent R₁₄Li and thetriflate derivatives is, generally speaking in the range ofapproximately −78° C. to 50° C. Compounds A10 and A13 and their analogscan be saponified, or subjected to further transformations, such ashomologation and other state-of-the-art reactions which yield homologsand derivatives in accordance with the reactions discussed above.

Reaction Scheme 2 serves as an example of synthetic methodology used forpreparing compounds of the present invention where the —Y(R₂)—A—B groupof Formulas 1-6 is linked to the tetrahydronaphthalene nucleus with thedesired Z group, before the final substitution pattern is obtained bytransformations of the tetrahydronaphthalene (or dihydronaphthalene)moiety.

Reaction Scheme 3 provides further examples for the synthesis ofcompounds within the scope of Formula 5 where the linking group betweenthe dihydronaphthalene moiety and the Y group is —CH═CH—. In thesequence of reactions described here the oxo function of a startingtetrahydronaphthalene-one moiety is modified before a Heck couplingreaction is performed. Specifically, in the example shown in thereaction scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G) is reacted with thiophenol in the presence of titaniumtetrachloride and triethylamine in tetrahydrofuran (THF), to provide theintermediate 4,4-dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene(Compound A35). A similar reaction can be performed with ethanethiol asa reagent instead of thiophenol, to yield2-bromo-5,6-dihydro-5,5-dimethyl-8-ethylthio-naphthalene (Compound A36)and other analogous compounds which are not shown in the reactionscheme. Compound A35 is reacted in the Heck reaction to yield ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-phenylthio-naphthalenyl)ethenyl]benzoate(Compound A16). Compound A16 is saponified to yield the carboxylic acid,(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]benzoicacid (Compound A18), and is oxidized with m-chloroperoxybenzoic acid(MCPBA) to provide the corresponding phenylsulfonyl compound, ethyl(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]benzoate(Compound A17). Compound A18 can also be oxidized under similarconditions to provide the free carboxylic acid (or salt thereof) of thephenylsulfonyl compound,(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-phenylsulfonyl-naphthalenyl)ethenyl]benzoicacid (Compound A19).

Reaction Scheme 4 discloses further examples for the preparation ofcompounds of the invention within the scope of Formula 2 where the grouplinking the tetrahydronaphthalene and Y(R₂)—A—B moieties is —CH═CH—. Asis shown in the scheme, ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethylnaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) is reacted with 1,3-propanedithiol in the presence ofborontrifluoride diethyl etherate to yield the corresponding cyclicthioketal compound, ethyl(E)-4-[-2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(1,3-dithian-2-yl)naphthalen-2-yl)ethenyl]benzoate(Compound A23). Other ketal and thioketal analogs of this compound,within the scope of Formula 2 can be obtained by analogous reactionssuitable for ketal and thioketal formation, which are per se well knownin the art. Saponification of Compound A23 provides the correspondingfree acid (or salt thereof),(E)4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(2-(1,3-dithian-2-yl)naphthalenyl)ethenyl]-benzoicacid (Compound A24).

Reaction Scheme 5 provides examples for the synthesis of compounds ofthe invention within the scope of Formula 3. The synthesis of thesecompounds proceeds in accordance with methodology where the desiredsubstituent is introduced into the tetrahydronaphthalene moiety beforethis moiety is coupled or linked to the desired Z—Y(R₂)—A—B group, andin these examples also the Z group is —CH═CH—. Thus in accordance withthis scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G) is reacted in a McMurry coupling reaction with acetone toprovide7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37). The reaction (McMurry coupling) is conducted at elevatedtemperature in the presence of lithium metal and titanium trichloride,in an inert ether type solvent, for example in refluxing1,2-dimethoxyethane (DME). In other examples which are described in theSpecific Examples, 3-pentanone, and cyclohexanone are used as ketonereagents, instead of the acetone shown in the reaction scheme. CompoundA37 is then subjected to a Heck coupling reaction with an ethenylreagent such as ethyl 4-vinylbenzoate shown in the scheme, to provideethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]benzoate(Compound A25). Compound A25 is saponified under conditions describedabove to provide(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]-benzoicacid (Compound A26).

Reaction Scheme 5 discloses another example for the preparation ofcompounds within the scope of Formula 3. In this example the substituentis introduced to replace the oxo function of tetrahydronaphthalene-2-oneafter the Z—Y(R₂)—A—B group has already been coupled to thetetrahydronaphthalene nucleus. Thus, ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H-one-2-yl)ethenyl]-benzoate(Compound A2) is reacted with ethyl bromoacetate in the presence of zincmetal in a Reformatsky reaction to provide (+/−) ethyl(E)4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate(Compound A32). Compound A32 is itself within the scope of the presentinvention, within the scope of Formula 1. Compound A32 is dehydrated, asshown in the example by treatment with (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent) to yield amixture of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate(Compound A33a), and ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H-anti(carbethoxymethylidenyl)-naphthalen-2-yl)ethenyl]benzoate (CompoundA33b). Compound A33a is within the scope of Formula 6, and Compound A33bis within the scope of Formula 3.

Reaction Scheme 6 provides examples for the synthesis of compounds ofthe invention where in accordance with Formulas 1-6 the Z group is—(CR₁═CR₁)_(n′)— and n′ is 0; in other words where there is no linkinggroup between the tetrahydronaphthalene or dihydronaphthalene nucleusand the Y(R₂)—A—B group. For the synthesis of these examples thestarting material is 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene(Compound F) which is reacted with n-butyl lithium andtriisopropylborate in an aprotic solvent such as toluene to give afterhydrolysis (5,6,7,8-tetrahydro-5,5-dimethylnaphth-2-yl)boronic acid(Compound B13). Compound B13 and related boronic acid derivatives (suchas Compound B14 in this, scheme) are suitable for coupling with areagent having the formula X₃-Y(R₂)—A—B where X₃ is halogen, and theremaining symbols are defined as for Formulas 1-6. Reaction Scheme 6illustrates this coupling reaction with ethyl6-bromo-naphthalene-2-carboxylate in the presence oftetrakis-triphenyl-phosphine palladium(0) to yieldethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-naphth-2-yl]naphthoate(Compound B1). Compound B1 of the invention is within the scope ofFormula 2. Other reagents corresponding to formula X₃—Y(R₂)—A—B arereadily available in accordance with the chemical literature and/or canbe obtained in accordance with state-of-the-art synthetic methodology.Examples for such other reagents are ethyl 4-bromobenzoate and ethyl2-bromopyridine-5-carboxylate.

Continuing on with the description of Reaction Scheme 6,6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene is reactedin the presence of base with t-butyldimethylsilyl chloride to provide6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-(t-butyldimethylsilyloxy)naphthalene(Compound B15). The starting6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene can beobtained by reduction of7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Underconditions similar to the ones described above Compound B15 is convertedto the boronic acid derivative(5,5-dimethyl-8-(t-butyldimethylsilyloxy)-5,6,7,8-tetrahydro-naphth-2-yl)boronicacid (Compound B14). Compound B14 is then coupled with ethyl6-bromo-naphthalene-2-carboxylate to yield ethyl6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-2-yl]naphth-2-oate(Compound B3). Compound B3 is then reacted with tetrabutylammoniumfluoride to remove the t-butyldimethylsilyl blocking group and to giveethyl6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-2-yl]naphth-2-oate(Compound B4). Compound B4 can be acylated to give ethyl6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(O-acetyl)-naphth-2-yl]naphth-2-oate(Compound B10), or methoxymethylated with methoxymethyl chloride in thepresence of base (preferably ethyl N,N-diisopropylamine, Hunig's base)to give ethyl6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-2-yl]naphth-2-oate(Compound B8), and oxidized with N-methyl morpholine N-oxide to provideethyl-6-[5,5-dimethyl-5,6-dihydro--naphthlen-8(7H)-one-2-yl]-naphthalen-2-oate(Compound B6). Compounds B8 and B10 of the invention are within thescope of Formula 1, whereas Compound B6 is within the scope of Formula2. Compound B6 can be converted into the O-methyloxime(ethyl6-[5,5-dimethyl-5,6-dihydro-naphthlen-8(7H)-anti-(O-methyl-oxime)-2-yl]-naphthalen-2-oate(Compound B11) not shown in the scheme) and into other derivatives suchas oximes, imines, hydrazones and the like, as is described above inconnection with Reaction Scheme 2. Further derivatives of Compound B6(and of analogous compounds) wherein the 8-oxo function of the moleculeis modified can be obtained in accordance with the general syntheticmethodology described in this specification. For example thetrifluoromethylsulfonyl (triflate) derivative can be obtained in analogyto the reaction leading to Compound A9 as described in Reaction Scheme2, and the trifluoromethylsulfonyl (triflate) derivative is reacted withthe reagents R₁₄Me to provide compounds of Formula 6.

Reaction Scheme 7 discloses a preferred example of a synthetic routeleading to compounds of the invention where with reference to Formulas1-6 the symbol Z represents —(CR₁═CR₁)_(n′)—, where n′ is 3, and thereis no Y(R₂) group. Thus,4,4-dimethyl-7-acetyl-1,2,3,4-tetrahydronaphthalen-1(2H)-one (CompoundD14a) is reacted in a Horner Emmons type reaction withtriethylphosphonoacetate in the presence of sodium hydride in an ethertype solvent such as tetrahydrofuran. Conditions of the Horner Emmonsreaction are well known in the art, and it is also well known thatusually a related Wittig type reaction can also be employed using atrialkylphosphonium reagent instead of the phosphonate reagent, to yieldthe same products as is obtained in the Horner Emmons reaction. Theproduct of the Horner Emmons reaction in this example is ethyl3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-enoate(Compound C2) which is reduced with diisobutyl aluminum hydride toprovide3-[1-hydroxy-4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-7-yl]but-2(E)-en-1-ol(Compound C3). Compound C3 is oxidized back to the aldehyde and ketone“stage” with manganese dioxide to give3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-en-al(Compound C4). Compound C4 is subjected to yet another Horner Emmonstype reaction with diethyl-(E)-3-ethoxycarbonyl-2-methylallylphosphonate(available from the chemical literature; see: Vuligunda et al. BiorganicMedical Chemistry Letters, (1996) 6 p213-218) in tetrahydrofuran in thepresence of n-butyl lithium, to yield ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5).

Compound C5 of the invention is within the scope of Formula 2, and isalso readily converted to further compounds of the invention inaccordance with the generic principles disclosed in this specification.Several examples of reactions which provide further compounds of theinvention using Compound C5 as the starting material are shown inReaction Scheme 7. These reactions are described in less detail to theextent that they are of the types which have been descibed above. Thus,the “oxo” compound ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5) is saponified to yield the free acid(not shown in the scheme), is converted to the O-methyl-oxime derivative(Compound C16); to ethyl7-[4,4-dimethyl-3,4-dihydro-1-(trimethylsiloxy)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(1-trimethylsilyloxy derivative Compound C28); and to ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (“triflate”, Compound C14). Compounds C14 and C28are within the scope of Formula 5, whereas Compound C16 is within thescope of Formula 4. Another Horner Emmons type reaction of Compound C5which leads to compounds within the scope of Formula 3 (Compounds 17aand 17B) is shown in the scheme.

In the examples shown in Reaction Scheme 7 the “oxo” compound ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5) is also reduced with ZnBH₄ to yieldthe corresponding secondary alcohol, ethyl7-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C13). Compound C13 is reacted withchloromethylmethyl ether to give (−/+)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C26); alternatively it is reacted with 3,4-dihydro-2H-pyran inmethylene chloride in the presence of p-toluene sulfonic acid (p-TsOH)to give the diastereomeric dihydropyranoxy derivatives, (+/−)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-naphth-2-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C29a) and (+/−)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(SR)-tetrahydropyranoxy)-naphth-2-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C29b). Compounds C13, C26, C29a and C29b of the invention arewithin the scope of Formula 1.

The trifluoromethylsulfonate (triflate) derivative Compound C14 isitself an important starting material for the syntheses of severalcompounds of the invention within the scope of Formula 6; among thesethe preparations of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C15) and of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-cyano-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound 21) are illustrated in the reactionscheme.

Reaction Scheme 8 discloses other examples for synthesizing preferredcompounds of the invention where with reference to Formula 5 the symbolZ represents —(CR₁═CR₁)_(n′)—, where n′ is 3, and there is no Y(R₂)group. The starting compound for the series of reactions shown in thisscheme is 4,4-dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene(Compound A35) which can be obtained as shown in Reaction Scheme 3.Thus, referring now to Reaction Scheme 8, Compound A35 is reacted with1-ethoxyvinyltributyltin (EVTB, available from Aldrich Chemical Co.) inthe presence of bis(triphenylphosphine)palladium(II)chloride intetrahydrofuran to provide, after acid work-up,4,4-dimethyl-7-acetyl-1-phenylthio-3,4-dihydronaphthalene (Compound C7).Compound C7 is subjected to a Horner Emmons reaction (as describedabove) with diethylcyanomethylphosphonate (available from AldrichChemical Co.) to provide3-[4,4-dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-nitrile(Compound C8). Compound C8 is reduced with diisobutyl aluminium hydrideto provide the corresponding aldehyde,3-[4,4-dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-aldehyde(Compound C9). Compound C9 is subjected to still another Horner Emmonsreaction with the reagentdiethyl-(E)-3-ethoxycarbonyl-2-methylallylphosphonate to yield ethyl7-[4,4-dimethyl-1-phenylthio-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C10). Compound C10 of the invention iswithin the scope of Formula 5.

In other preferred examples not shown in the schemes but described inthe Specific Examples, a sequence of reaction which is analogous to theabove-described reactions of Reaction Scheme 8 is conducted, startingwith 7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37), or with7-bromo-1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C37) to provide further examples for compounds of theinvention, such asethyl-7-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethyl-naphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)-trienoate(Compound C36) and ethyl7-[4,4-dimethyl-3,4-dihydro-1(2H)-phenylbenzylidenyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C41). Compounds C36 and C41 of the invention are within thescope of Formula 3.

Compound C10 is converted by oxidation with meta-chloroperoxybenzoicacid to the corresponding sulfone and sulfoxide, ethyl7-[4,4-dimethyl-1-phenylsulfonyl-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C11a) and ethyl7-[4,4-dimnethyl-1-phenylsulfoxide-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C11b), which are also within the scope of Formula 5.

Reaction Scheme 9 discloses the preferred method of synthesis of astarting material from which certain examples for compounds of theinvention within the scope of Formula 6 are preferably made. Inaccordance with this scheme7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) isreacted with t-butylmagnesium chloride in tetrahydrofuran in thepresence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-pyrimidinone (DMPU).Thereafter, the resulting intermediate tertiary alcohol is heated in thepresence of acid (p-toluenesulfonic acid) to give7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethyl naphthalene(Compound C42). Compound C42 is reacted with 1-ethoxyvinyltributyltin(EVTB) in the presence of Pd(0) catalyst to yield after acidic work-up7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C43). Compound C43 is subjected to a sequence of reactions ofthe type described above in connection with Reaction Scheme 8, startingwith a Horner Emmons reaction with diethyl cyanomethylphosphonate, toeventually provide ethyl7-[4,4-dimethyl-3,4-dihydro-1-(1,1-dimethylethyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C46). Compound C46 of the invention is within the scope ofFormula 6.

Reaction Scheme 10 discloses a preferred synthetic route to certainexamplary compounds of the invention where, with reference to Formulas1-6 the Z group is —N═N— (azo) moiety. For the examples shown in thisscheme the starting compound is3,4-dihydro-4,4-dimethyl-7-amino-naphthalen-1(2H)-one (Compound D9).Compound D9 is coupled with a nitroso compound of the formulaON—(R₂)—A—B, which in the herein shown example is ethyl4-nitrosobenzoate (available in accordance with the chemical literature;see Kagechika et al. J. Med. Chem. (1989) 32, 1098-1108). The couplingreaction is conducted in glacial acetic acid and yields ethyl4-[(5,6-dihydro-5,5-dimethyl-8(7H)-one-naphthalen-2-yl)azo]-benzoate(Compound D10). Compound D10 of the invention is within the scope ofFormula 2. Compound D10 is reacted in a Reformatsky reaction with ethylbromoacetate to provide (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate(Compound D1). Compound D1 of the invention is within the scope ofFormula 1. Dehydration of Compound D1 with dicyclohexylcarbodiimide andcuprous chloride in benzene provides the isomeric compounds ethyl4-[(5,5-dimethyl-8(7H)-(carbethoxymethylidenyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2a) and ethyl4-[(5,5-dimethyl-8-(carbethoxymethyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2b). Compound D2a of the invention is within the sope ofFormula 3, and Compound D2b is within the scope of Formula 6.

The “oxo” compound ethyl4-[(5,6-dihydro-5,5-dimethyl-8(7H)-one-naphthalen-2-yl)azo]-benzoate(Compound D10) serves as starting material for reactions which lead tofurther compounds of the invention in accordance with syntheticmethodology that has been described above. More particularly, in theexamples shown in Reaction Scheme 10 Compound D10 is converted into theO-methyl oxime derivative ethyl 4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoate (CompoundD3), into the “triflate” ethyl4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-naphthalen-2-yl)azo]-benzoate(Compound D11) and is reduced to the secondary alcohol (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound DS). The O-methyl oxime derivative (Compound D3) of theinvention is within the scope of Formula 4, the “triflate” Compound D11is in the scope of Formula 5, whereas the secondary alcohol Compound D5is within the scope of Formula 1.

The secondary alcohol, Compound D5 is further converted into themethoxymethyl derivative (+/−) ethyl4-[(5,5-dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D6) within the scope of Formula 1, and the “triflate” isreacted with thienyl lithium in the presence of ZnCl₂ and Pd(0) catalystto provide ethyl4-[(5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D12).

Referring now to Reaction Scheme 11 a preferred example for thesynthesis of those compounds of the invention is described where, withreference to Formulas 1-6 the Z group is —CO—CR₁═CR₁—. As it will becomeapparent from the reaction scheme, these compounds are obtained as aresult of an aldol condensation between an appropriately substitutedtetrahydro or dihydronaphthalene ketone derivative and an aldehyde ofthe formula OCH—Y(R₂)A—B. In the example shown in Reaction Scheme 11 theexocyclic ketone function of3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (Compound D14b)is reacted with ethylene glycol and acid to provide6-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15) where one ketone function is protected. Compound D15 isthen reacted with ethyl bromoacetate in a Reformatsky reaction to give(+/−)6-(2-methyl-1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene(Compound D16). Treatment with acid of Compound D16 removes the1,3-dioxolanyl protecting group and also introduces a double bond intothe tetrahydronaphthalene nucleus, thus providing3,4-dihydro-4,4-dimethyl-1-(carbethoxymethyl)-6-acetyl-naphthalene(Compound D17).

An alternate method for obtaining dihydronaphthalene compounds havingthe 6-acetyl substituent and a substituent in the 1-position (attachedto the vinylic carbon) is to react Compound D15 with sodiumbis(trimethylsilyl)amide and2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in an inertether type solvent, such as tetrahydrofuran, at low temperatures (−78°C. and 0° C.). As noted above in connection with an analogous “triflate”forming reaction, this reaction proceeds through a sodium saltintermediate which is usually not isolated. The overall reaction resultsin a trifluoromethylsulfonyloxy derivative, which is therafter reactedwith an organometal derivative, again in analogy to the precedingdescription of synthesizing compounds of Formula 6 from the “triflate”derivatives.

Returning now to the description of Reaction Scheme 11, Compound D17 isreacted with 4-carboxybenzaldehyde in an aldol condensation reaction togive ethyl(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(carbethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoate(Compound D18). The just described aldol condensation reaction isconducted in the presence of base in an alcoholic solvent. Preferably,the reaction is conducted in methanol or ethanol in the presence ofsodium hydroxide. Those skilled in the art will recognize the aldolcondensation reaction of this example as a Claisen-Schmidt reaction.(See March: Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, pp 694 695 McGraw Hill (1968). Examples of other reagents isanalogous to 4-carboxybenzaldehyde and suitable for the condensationreaction to introduce heterocyclic Y(R₂) groups into the compounds ofthe present invention 1) are: 5-carboxypyridine-2-carboxaldehyde,4-carboxypyridine-2-carboxaldehyde, 4-carboxythiophene-2-carboxaldehyde,5-carboxythiophene-2-carboxaldehyde, 4-carboxyfuran-2-carboxaldehyde,5-carboxyfuran-2-carboxaldehyde, 4-carboxyacetophenone,2-acetylpyridine-5-carboxylic acid, 2-acetylpyridine-4-carboxylic acid,2-acetyl-thiophene-4-carboxylic acid, 2-acetylthiophene-5-carboxylicacid, 2-acetylfuran-4-carboxylic acid, and 2-acetylfuran-5-carboxylicacid. The latter compounds are available in accordance with the chemicalliterature; see for example Decroix et al., J. Chem. Res.(S), 1978 4,134; Dawson et al., J. Med. Chem., 1983, 29, 1282; and Queguiner et al.,Bull Soc. Chimique de France, 1969, No. 10, pp 3678-3683. Compound D18of the invention is within the scope of Formula 6.

To obtain further preferred examples of the compounds of the inventionwhere the Z group is —CO—CR₁═CR₁— the aldol condensation reaction shownin Reaction Scheme 11 is performed on the following compounds:

3,4-dihydro-4,4-dimnethyl-6-acetyl-1-(1,1-dimethylethyl)naphthalene(Compound D19);

6-Acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound D22);

(+/−)1-(methoxymethyloxy)-6-acetyl-1,2,3,4-tetrahydro-4,4-dimnethylnaphthalene(Compound D26); and

6-Acetyl-1(2H)-(O-methyl oxime)-3,4-dihydro-4,4-dimethylnaphthalene(Compound D28)

to provide respectively the following examples of compounds of theinvention:

(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(1,1-dimethyl-ethyl)naphth-6-yl)-prop-1-en-3-one]benzoicacid (Compound D20, Formula 6);

(E)-4[3-{1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicacid (Compound D23, Formula 3);

(E)-4-[3-(1,2,3,4-tetrahydro-4,4-dimethyl-1-(methoxymethyloxy)naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D27, Formula 1), and

(E)-4[3-{1(2H)-(O-methyloxime)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicacid (Compound D29, Formula 4).

Reaction Scheme 12 discloses the presently preferred methods forsynthesizing preferred examples of compounds of the invention where withreference to Formulas 1-6 the Z group is —COO— or —CONH—. As is shown inthe scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G) is reacted with carbon monoxide in the presence ofpalladium(II)-bis(triphenylphosphine)chloride,1,3-bis(diphenylphosphino)-propane, DMSO, methanol and triethylamine toobtain the corresponding carboxylic acid methyl ester, methyl5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (CompoundE2), which is thereafter saponified to provide5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylic acid(Compound E3). Compound E3 is a free carboxylic acid which is reactedeither with compounds of the formula H₂N—Y(R₂)—A—B to provide compoundsof the invention where Z is —CONH—, or with compounds of the formulaHO—Y(R₂)—A—B to provide compounds of the invention where Z is —COO—.Those skilled in the art will recognize that these compounds of theinvention are amide and ester compounds, respectively. Generallyspeaking several known methods for amide and ester formation may beemployed for their synthesis from Compound E3 or analogous carboxylicacid compounds. For example, Compound E3 or analogous carboxylic acidcompounds can be converted into the acid chloride by known methods andthereafter reacted with the amines or esters of formula H₂N—Y(R₂)—A—B orformula HO—Y(R₂)—A—B respectively. The presently preferred method forsynthesis, however utilizes the reagents1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and4-N)N-dimethylaminopyridine in an aprotic solvent for the amide or esterformation. Those skilled in the art will also recognize that thecompounds of formula H₂N—Y(R₂)—A—B and formula HO—(R₂)—A—B are aromaticor heteroaromatic amines or hydroxyl derivatives, which can be obtainedin accordance with the state-of-the-art.

Referring now back to Reaction Scheme 12 that describes certainpreferred specific examples, 5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylic acid (Compound E3) is reacted in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and4-(dimethylamino)pyridine in methylene chloride to give ethyl4-[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound 28). Compound 28 of the invention is in the scope of Formula2. Reaction Scheme 12 discloses its conversion by reactions of the typedescribed above, to ethyl4-[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E30, Formula 4) and (+/−)4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E32, Formula 1). Compound E32 is converted to themethoxymethyl derivative (+/−) ethyl4-[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E34) within the scope of Formula 1. Each of these amidecompounds can have their respective COOEt group saponified to providethe free carboxylic acid or its salt.

Referring still to Reaction Scheme 12, methyl5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (CompoundE2) is converted, under conditions described above for analogousreactions, into the trifluoromethylsulfonyl (“triflate”) derivative,methyl5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate(Compound E4). Compound E4 serves as an important intermediate for thesynthesis of compounds within the scope of Formula 6. In the preferredexamples shown in the reaction scheme, Compound E4 is reacted with thelithium derivative of thiophene in the presence of ZnCl₂ and Pd(0)catalyst to provide the thienyl substituted carboxylic acid methylester, (Compound E5). The latter compound is saponified to give5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6). Compound E6 is coupled with ethyl 4-aminobenzoate to giveethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E7), and with ethyl 4-hydroxybenzoate to provide ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E9). Compounds E7 and E9 of the invention are within the scopeof Formula 6.

As it will be readily recognized in the art, the free carboxylic acidderivatives of the invention could not be obtained (or could be obtainedonly with difficulty) from the carbonyloxy compounds of the presentinvention by a process of saponification of the ester compounds such asCompound E9. However, the above-mentioned free carboxylic acids, such as4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoicacid (Compound E11) can be obtained from the corresponding2-(trimethylsilyl)ethyl esters (such as 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate,(Compound E10) by treatment with tetrabutylammonium fluoride. CompoundE10 and like compounds can be obtained by coupling reactions of the typedescribed above, utilizing, for example, 2-trimethylsilylethyl4-hydroxybenzoate. The latter reactions are not shown in Reaction Scheme12 but specific examples are described below.

5,5-Dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylic acid(Compound E3) is also coupled with ethyl 4-hydroxybenzoate to provideethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44) within the scope of Formula 2. Compound E44 is subjectedto a Reformatsky reaction with ethyl bromoacetate to yield (+/−) ethyl4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E54). Although the following reactions are not shown in thescheme, an additional preferred example of compounds of the invention isobtained when Compound E44 is reduced with sodium borohydride to giveethyl4-[[(5,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E40). The latter is converted into tetrahydropyranylderivatives (within the scope of Formula 1) as is disclosed in detail inthe Specific Examples.

To obtain still more specific examples for the compounds of theinvention where the Z group is —COO— or —CONH—7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) issubjected to a Reformatsky reaction with ethyl bromoacetate, and theresulting (+/−) ethyl2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound 47) is subjected to the series of reactions shown in ReactionScheme 12. These compounds, although not specifically shown in thescheme, are disclosed in detail in the appended Specific Examples.

Reaction Scheme 13 discloses examples for the synthesis of severalpreferred compounds of the invention within the scope of Formula 3. Thereactions shown in this scheme are analogous to the reactions disclosedin the foregoing description and reaction schemes and therefore will bereadily understood by those skilled in the art and do not requirefurther explanation here. A detailed experimental description for thepreparation of compounds shown in this scheme is provided in thedescription of the Specific Examples. The same applies to ReactionScheme 14, which discloses examples for the synthesis of severalpreferred compounds of the invention within the scope of Formula 5.

Compounds of the invention where with reference to the Formulas 1-6 theZ group is —N(O)═N— or —N═N(O)— can be prepared by oxidation ofcompounds where the Z group is —N═N—. A suitable is oxidizing agent forthis purpose is meta-chloroperoxybenzoic acid; typically both isomers ofthe azoxy compounds are formed in reactions using this agent.

Compounds of the present invention where with reference to Formula 1-6,Z is —OCO—, NR₁CO, as well as the corresponding thioester and thioamideanalogs, can be prepared from the intermediates having a bromo functionon the aromatic portion of the tetrahydronaphthalene ordihydronaphthalene nucleus, for example such as Compounds G, H, A35,A37, B15 and C42. In these compounds the bromo function is replaced withan amino or hydroxyl group, in analogy to the teachings of U.S. Pat.Nos. 5,324,744, the specification of which is expressly incorporatedherein by reference.

Compounds of the present invention where with reference to Formula 1-6,Z is —N═CR₁— or —CR₁═N— will be readily recognized by those skilled inthe art as Schiff bases. These compounds can be made by reaction betweena primary amine and aldehyde or ketone. In order to obtain thesecompounds where the Z is —N═CR₁— an amine of the structure where the NH₂group is attached to the aromatic portion of the tetrahydronaphthaleneor dihydronaphthalene nucleus, is reacted with an aldehyde or ketone ofthe structure OCR₁—Y(R₂)—A—B. An example for such an amine is CompoundD9. Schiff bases of the structure where Z is —CR₁═N— can be obtained byreaction of an amine of the formula NH₂—Y(R₂)—A—B with an aldehyde orketone where the aldehyde or ketone function is attached to the aromaticportion of the tetrahydronaphthalene or dihydronaphthalene nucleus.Compounds D14a and D14b serve as examples.

Compounds of the present invention where with reference to Formula 1-6,the X₁ group is [C(R₁)₂]_(n) and n is zero (0), can be made startingwith 6-bromo-indan-1-one (or an appropriately subtituted derivative). Inthese synthetic schemes 6-bromo-indan-1-one is used in analogy to7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) as astarting material. 6-bromo-3,3-dimethyl-indan-1-one is availableaccordance with the chemical literature. (See Smith, J. G.,; Massicotte,M. P. Org. Prep. Proced. Int., 1978, 10 123-131.)

Compounds of the invention where with reference to Formula 1-6, the X₁group is [C(R₁)₂]_(n) and n is 2 can be made from8-bromo-2,3,4,5-tetrahydro-5,5-dimethyl-1-(2H)-suberan-one (Compound F7)which is used as a starting material in analogy to Compound G. CompoundF7 can be made in accordance with the reaction sequence shown inReaction Scheme 15. As is shown in the scheme,(3-bromophenyl)acetaldehyde (Compound F1) is subjected to a Wittigreaction to obtain a 5 carbon chain attached to the aromatic nucleus,and the resulting Compound F2 is hydrogenated and subjected to Jonesoxidation followed by esterification, to provide methyl(3-bromophenyl)-pentanoate (Compound F4). Compound F4 is reacted with aGrignard reagent to provide a tertiary alcohol (Compound F5), which iscyclized to provide 8-bromo-2,3,4,5-tetrahydro-5,5-dimethyl-suberan(Compound F6). Compound F6 is oxidized with CrO₃ to yield8-bromo-2,3,4,5-tetrahydro-5,5-dimethyl-1-(2H)-suberan-one (CompoundF7).

SPECIFIC EXAMPLES Ethyl (4-bromophenyl)Acetate (Compound A)

A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g ofconc. H₂SO₄ in 470 ml of ethanol was refluxed for 16 hours. The reactionmixture was cooled to ambient temperature, stirred with 6 g of solidK₂CO₃ for 30 minutes and then filtered. The filtrate was concentrated invacuo, diluted with Et₂O (200 ml), washed with 10% aqueous NaHCO₃ (10ml) and brine (10 ml), dried over MgSO₄ and concentrated in vacuo togive the title compound as a colorless oil. PMR (CDCl₃) δ 1.25 (3H, t,J=7.0 Hz), 3.56 (2H, s), 4.15 (2H, q, J=7.0 Hz), 7.16 (2H, d, J=8.4 Hz),7.45 (2H, d, J=8.4 Hz).

Ethyl (3-bromophenyl)Acetate (Compound B)

Employing the same general procedure as for the preparation of ethyl(4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of3-bromophenylacetic acid was converted into the title compound (yellowoil) using 2 g of conc. H₂SO₄ and 500 ml of ethanol. PMR (CDCl₃): δ 1.26(3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.16-7.26 (2H,m), 7.38-7.46 (2H, m).

Ethyl 4-(4-bromophenyl)Butanoate (Compound C)

To a cold solution (−78° C.) of 15 g (62 mmol) of ethyl(4-bromophenyl)acetate (Compound A) in 150 ml of CH₂Cl₂ was addeddropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminumhydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition wascomplete, the reaction was stirred at −78° C. for an additional hour.The reaction was quenched by the dropwise addition of methanol (10 ml),followed by water (10 ml) and 10% HCl (40 ml). The mixture was thenwarmed to 0° C., stirred for 10 minutes and then washed with water (15ml), 10% aqueous NaHCO₃ (10 ml) and brine (10 ml). The organic phase wasdried over MgSO₄ and the solvent distilled off at ambient temperature togive crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) ofthis crude aldehyde in 150 ml of CH₂Cl₂ was added a solution of 26 g(74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml ofCH₂Cl₂. The mixture was stirred for 16 hours, concentrated in vacuo andpurified by flash chromatography (silica, 10% EtOAc-hexane) to giveethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. Thisisomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and thefiltrate concentrated in vacuo to give the title compound as a whitesolid.

PMR (CDCl₃): δ 1.26 (3H, t, J=7.1 Hz), 1.88-1.99 (2H, m), 2.31 (2H, t,J=7.5 Hz), 2.61 (2H, t, J=7.5 Hz), 4.28 (2H, q, J=7.1 Hz), 7.05 (2H, d,J=8.4 Hz), 7.40(2H, d, J=8.4 Hz).

Ethyl 4-(3-bromophenyl)Butanoate (Compound D)

Employing the same general multistep preparation as for ethyl4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl(3-bromophenyl)acetate (Compound B) was converted into the titlecompound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride(DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of(carbethoxymethylene)triphenylphosphorane and 1.7 g of 10% Pd/C. PMR(CDCl₃): δ 1.26 (3H, t, J=7.1 Hz), 1.89-2.00 (2H, m), 2.31 (2H, t, J=7.5Hz), 2.63 (2H, t, J=7.2 Hz), 4.15 (2H, q, J=7.1 Hz), 7.10-7.35 (4H, m).

5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E)

To a cold solution (0° C.) of 17 g (63 mmol) of ethyl4-(3-bromophenyl)butanoate (Compound D) in 40 ml of THF was added 63 ml(189 mmol) of methylmagnesium bromide (3.0M solution in THF). Thereaction was stirred at 0° C. for 2 hours, quenched by the slow additionof ice cold water (30 ml) followed by 10% HCl (30 ml) and then extractedwith Et₂O (4×60 ml). The combined organic layer was washed with 10%aqueous NaHCO₃ (10 ml), water (10 ml) and brine (10 ml), dried overMgSO₄ and concentrated in vacuo. Purification by Kugelrohr distillationgave the title compound as a colorless oil.

PMR (CDCl₃) δ 1.20 (6H, s), 1.43-1.55 (2H, m), 1.62-1.78 (2H, m), 2.60(2H, t, J=6.0 Hz), 7.10-7.41 (4H, m).

6-Bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F)

15.0 g (58.3 mmol) of 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E)was cooled to 0° C. and then 2.8 ml of conc. H₂SO₄ was added. Themixture was stirred for 2.5 hours, diluted with water (20 ml) andextracted with Et₂O (3×40 ml). The combined organic layers were washedwith water, sat. aqueous NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. Purification by Kugelrohr distillation gave thetitle compound as a colorless oil.

PMR (CDCl₃): δ 1.25 (6H, s), 1.61-1.66 (2H, m), 1.74-1.82 (2H, m), 2.73(2H, t, J=6.0 Hz), 7.16-7.26 (3H, m).

7-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H-one (Compound G)

To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acidwas added a solution of 10 g (41.8 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125ml of benzene. The reaction mixture was stirred for 1 hour, quenchedwith ice cold water and extracted with Et₂O (3×100 ml). The organiclayer was dried over MgSO₄, concentrated in vacuo, and purified bycolumn chromatography (silica, 10% EtOAc-hexane) to give the titlecompound as a white solid.

PMR (CDCl₃): δ 1.28 (6H, s), 2.01 (2H, t, J=6.0 Hz), 2.72 (2H, t, J=6.0Hz), 7.31 (1H, d, J=9.0 Hz), 7.61 (1H, dd, J=3.0, 9.0 Hz), 8.11 (1H, d,J=3.0 Hz).

6-Bromo-3,4-dihydro-4,4-ditmethylnaphthalen-1(21)-one (Compound H)

Employing a published procedure (Mathur, N. C.; Snow, M. S.; Young, K.M.; and Pincock, J. A. Tetrahedron. 41, 1509-1516 (1985)), ethyl4-(4-bromophenyl)butanoate (Compound C) was converted into the titlecompound. Alternatively, the title compound can be obtained usingsimilar reactions that were used to convert ethyl4-(3-bromophenyl)butanoate (Compound D) into7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G)

Ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2)

To a solution of 520.0 mg (2.00 mmol) of3,4-dihydro-4,4-dimethyl-7-bromo-naphthalen-1(2H)-one (Compound G), and510.0 mg (2.90 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine(degassed by sparging with argon for 25 minutes), was added 124.0 mg(0.40 mmol) of tris(2-methylphenyl) phosphine, followed by 44.0 mg (0.20mmol) of palladium(II)acetate. The resulting solution was heated to 95°C. for 2.5 h, cooled to room temperature, and concentrated under reducedpressure. Purification by column chromatography (10% EtOAc/hexanes)afforded the title compound as a colorless solid.

¹H NMR (CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 1.41 (s, 6H), 2.04 (t, J=6.5Hz, 2H), 2.76 (t, J=6.5 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.20 (s, 2H),7.45 (d, J=8.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.69 dd, J=2.0, 8.2 Hz,1H), 8.03 (d, J=8.4 Hz, 2H), 8.19 (d, J=2.0 Hz, 1H).

(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxo-2-naphthalenyl)ethenyl]-BenzoicAcid (Compound A2a)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoic acid (Compound A4) 110 mg (0.32mmol) of ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxo-2-naphthalenyl)ethenyl]-benzoate(Compound A2) was converted into the title compound using 1.0 mL (1.5mmol) of LiOH (1.5 M aqueous solution) and 0.5 mL of methanol.

1H NMR (DMSO) δ 1.36 (s, 6H), 1.96 (t, J=6.7 Hz, 3H), 2.69 (t, J=6.7 Hz,2H), 7.35 (d, J=16.4 Hz, 1H), 7.49 (d, J=16.4 Hz, 1H), 7.58 (d, J=8.4Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.89 (overlapping d, 3H), 8.05 (s, 1H).

Ethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methylOxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3)

A solution of 298 mg (0.85 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2), 290 mg (3.4 mmol) of methoxylamine hydrochloride and 610mg (4.5 mmol) of sodium acetate in 7.0 mL of EtOH and 5.0 mL oftetrahydrofuran was stirred at ambient temperature for 96 h and refluxedfor 3 h. An additional 0.24 g (1.8 mmol) of methoxylamine hydrochloridewas added and the mixture refluxed for another 1 h. The mixture wasconcentrated in vacuo, the residue was diluted with water and extractedwith EtOAc (2×). The combined organic layer was dried over MgSO₄, andconcentrated in vacuo. The crude material was purified by flashchromatography (silica, 5% ethyl acetate in hexanes) to afford the titlecompound as a yellow oil.

¹H NMR (CDCl₃): δ 1.30 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 1.73 (t, J=6.9Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 4.04 (s, 3H), 4.39 (q, J=7.1 Hz, 2H),7.13 (d, J=16.4 Hz, 1H), 7.22 (d, J=16.4 Hz, 1H), 7.36 (d, J=8.2 Hz,1H), 7.50 (dd, J=2.0, 8.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 8.03 (d,J=8.4 Hz, 2H), 8.11 (d, J=2.0 Hz, 1H).

(E)-4-[2-(5,5-Dimethyl-5,6,-dihydro-8(7H)-anti-(O-methylOxime)-naphthalen-2-yl)ethenyl]-Benzoic Acid (Compound A4)

To a solution of 183 mg (0.48 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3) in 4.0 mL oftetrahydrofuran and 1.0 mL of methanol was added 1.0 mL (2.4 mmol) ofLiOH (2.4 M aqueous solution). The mixture was stirred at ambienttemperature for 19 h, and concentrated in vacuo. The residue was dilutedwith water and acidified to pH 1 with 10% HCl and extracted with ethylacetate (2×). The organic phase was washed with brine, dried with MgSO₄and concentrated in vacuo. Recrystallization of the crude product usingacetonitrile afforded the title compound as white crystals.

¹H NMR (DMSO-D₆): δ 1.24 (s, 6H), 1.66 (t, J 6.6 Hz, 2H), 2.72 (t, J=6.6Hz, 2H), 3.95 (s, 1H), 7.26 (d, J=16.5 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H),7.44 (d, J=16.5 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.74 (d, J=8.1 Hz, 2H),7.92 (d, J=8.1 Hz, 2H), 8.01 (s, 1H).

Ethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-ethylOxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A5)

Employing the same general procedure as for the preparation of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3) 146 mg (0.42mmol) of ethyl (E)-4-[2-(5,5-dimethyl-5,6,dihydronaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2) wasconverted into the title compound (white solid) using 167 mg (1.7 mmol)of ethoxylamine hydrochloride, 337 mg (2.5 mmol) of sodium acetate, 5.0mL of EtOH and 1.0 mL of tetrahydrofuran.

¹H NMR (CDCl₃): δ 1.28 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.39 (t, J=7.1Hz, 3H), 1.71 (t, J=6.9 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 4.27 (q, J=7.1Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.11 (d, J=16.4 Hz, 1H), 7.21 (d,J=16.4 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.48 (dd, J=1.9, 8.2 Hz, 1H),7.55 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 8.11 (d, J=1.9 Hz, 1H).

(E)-4-[2-(5,5-Dimethyl-5,6,-dihydro-8(7H)-anti-(O-ethylOxime)-naphthalen-2-yl)ethenyl]-Benzoic Acid (Compound A6)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 81 mg (0.21mmol) of ethyl (E)4-[2-(5,5-dimethyl-5,6-dihydro-8(7H)-anti-(O-ethyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A5) was convertedinto the title compound (white solid) using 1.0 mL (1.8 mmol) of LiOH(1.8 M aqueous solution).

¹H NMR (Acetone-D₆): δ 1.30 (s, 6H), 1.31 (t, J=7.1 Hz, 3H), 1.73 (t,J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 7.30 (d,J=16.4 Hz, 1H), 7.41 (d, J=16.4 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.66(dd, J=1.9, 8.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H),8.15 (d, J=1.9 Hz, 1H).

Ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(72)-anti-(oxime)-naphthalen-2-yl)ethenyl]-benzoate(Compound A7)

Employing the same general procedure as for the preparation of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3) 190 mg (0.55mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6-dihydronaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) was converted into the title compound using 152 mg (1.7mmol) of hydroxylamine hydrochloride, 430 mg (3.2 mmol) of sodiumacetate, 6.0 mL of EtOH and 1.0 mL of tetrahydrofuran.

¹H NMR (CDCl₃): δ 1.32 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 1.77 (t, J=7.0Hz, 2H), 2.91 (t, J=7.0 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.13 (d, J=16.4Hz, 1H), 7.20 (d, J=16.4 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.49 (m, J=1.8Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 8.08 (d, J=1.8Hz, 1H), 8.48 (s, 1H).

(E)-4-[2-(5,5-Dimethyl-5,6,-dihydronaphthalen-8(7H)-anti(oxime)-2-yl)ethenyl]-BenzoicAcid (Compound A8)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 104 mg (0.29mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(oxime)-naphthalen-2-yl)ethenyl]-benzoate(Compound A7) was converted into the title compound using 1.0 mL (1.5mmol) of LiOH (1.5 M aqueous solution).

¹H NMR (DMSO-D₆): δ 1.24 (s, 6H), 1.66 (t, J=6.7 Hz, 2H), 1.71 (t, J=6.7Hz, 2H), 7.23 (d, J=16.5 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.42 (d,J=16.5 Hz, 1H), 7.62 (dd, J=1.7, 8.3 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H),7.92 (d, J=8.5 Hz, 2H), 8.03 (d, J=1.7 Hz, 1H).

Ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-naphthalen-2-yl)ethenyl]-benzoate (Compound A9)

To a cold (−78 ° C.) solution of 440.0 mg (2.40 mmol) of sodiumbis(trimethylsilyl)amide in 10.0 mL of THF was added 700.0 mg (2.00mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) as a solution in 25.0 mL of THF. After stirring at −78° C.for 1.5 h, 960.0 mg (2.40 mmol) of 2[N,N-bistrifloromethylsulfonyl)amino]-5-chloropyridine was added in one portion.After 30 min, the solution was warmed to 0° C. and stirred for 3 h. Thereaction was quenched by the addition of saturated aqueous NH₄Cl, andextracted with EtOAc. The combined extracts were washed with 5% aqueousNaOH, dried (NaSO₄), and the solvents removed under reduced pressure.The title compound was isolated as a colorless solid after columnchromatography (7% EtOAc/hexanes).

¹H NMR (CDCl₃): δ_(—)1.32 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 2.43 (d,J=4.9 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 6.00 (t, J=4.9 Hz, 1H), 7.10 (d,J=16.4 Hz, 1H), 7.20 (d, J=16.4 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.49(d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.4Hz, 1H).

Ethyl(E)-4-[2-(5,5-dimethyl-8-(thiazol-2-yl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoate(Compound A10)

To a cold (−78° C.) solution of thiazole (0.38 g (0.10 mL, 1.4 mmol) inTHF (2.0 mL) was added n-butyl lithium (1.6 M solution in hexanes, 0.5mL, 0.8 mmol) and stirred for 30 min. To this solution was added 0.176 g(1.3 mmol) of zinc chloride in 3.0 mL of tetrahydrofuran and stirred for45 min. The resulting turbid solution was transferred, via cannula, to aflask containing a mixture of 0.17 g (0.35 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-5,6-dihydronaphthalen-2-yl)ethenyl]benzoate(Compound A9) and 15 mg (0.01 mmol) oftetrakis(triphenylphosphine)palladium(0) in 3.0 mL of tetrahydrofuran.The reaction mixture was stirred for 1 h at ambient temperature and 1.5h at 55° C. The reaction mixture was treated with aqueous NH₄Cl, andextracted with EtOAc (2×). The combined organic layer was washed withbrine and dried (MgSO₄). The solvent was removed under reduced pressureand the crude product was purified by flash chromatography (silica, 20%ethyl acetate in hexane) to afford the title compound as a white solid.

¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.41 (d, J=4.9Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.56 (t, J=4.9 Hz, 1H), 7.03 (d, J=16.4Hz, 1H), 7.18 (d, J=16.4 Hz, 1H), 7.34 (d, J=3.4 Hz, 1H), 7.38 (d, J=8.1Hz, 1H), 7.48 (dd, J=1.8, 8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.86 (d,J=1.8 Hz, 1H), 7.93 (d, J=3.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H).

(E)-4-[2-(-5,5-Dimethyl-8-(thiazol-2-yl)-5,6-dihydronaphthalen-2-yl)ethenyl]-BenzoicAcid (Compound A12)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 20 mg (0.05mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(thiazol-2-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A10) was converted into the title compound (white solid).

¹H NMR (CDCl₃): δ 1.28 (s, 6H), 2.39 (d, J=4.9 Hz, 2H), 6.63 (t, J=4.9Hz, 1H), 7.15 (d, J=16.4 Hz, 1H), 7.36 (d, J=16.4 Hz, 1H), 7.43 (d,J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.77 (d,J=3.3 Hz, 1H), 7.90 (m, J=8.2 Hz, 3H), 7.97 (d, J=3.3 Hz, 1H).

Ethyl(E)-4-[2-(-5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoate(Compound A13)

A solution of lithiothiophene was prepared by the addition of 0.10 g(0.095 mL, 1.2 mmol) of thiophene to a cold solution (−78° C.) of 0.61 g(0.90 mL, 1.4 mmol, 1.6 M in hexanes) of n-butyl lithium in 2.0 mL oftetrahydrofuran. The solution was stirred at −78° C. for 35 min and thena solution of 0.158 g (1.2 mmol) of zinc chloride in 2.0 mL oftetrahydrofuran was added. The resulting solution was stirred at −78° C.to room temperature for 1 h and then the organozinc was added viacannula to a mixture of 0.212 g (0.44 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-5,6-dihydronaphthalen-2-yl)ethenyl]benzoate(Compound A9) and 18 mg (0.016 mmol) oftetrakis(triphenylphosphine)palladium(0) in 2.0 mL of tetrahydrofuran.The resulting mixture was stirred at room temperature for 10 min andthen heated at 50° C. for 1 h. The reaction was quenched by the additionof sat. aqueous NH₄Cl. The mixture was extracted with EtOAc (2×), andwashed with brine. The organic phase was dried over Na₂SO₄ and thenconcentrated in vacuo. The crude material product was purified by flashchromatography (silica, 15% ethyl acetate in hexanes) to afford thetitle compound as a solid.

¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.34 (d, J=4.8Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.22 (t, J=4.8 Hz, 1H), 7.02 (d, J=16.4Hz, 1H), 7.10-7.12 (m, 2H), 7.15 (d, J=16.4 Hz, 1H), 7.29-7.33 (m, 1H),7.37 (d, J=8.0 Hz, 1H), 7.45 (dd, J=1.8, 8.0 Hz, 1H), 7.52 (d, J=8.5 Hz,2H), 7.53 (d, J=1.8 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H).

(E)-4-[2-(-5,5-Dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)ethenyl]-BenzoicAcid (Compound A15)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 98 mg (0.24mmol) of ethyl(E)-4-[2-(-5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoate(Compound A13) was converted into the title compound (white solid).

¹H NMR (DMSO-D₆): δ 1.27 (s, 6H), 2.32 (d, J=4.8 Hz, 2H), 6.23 (t, J=4.8Hz, 1H), 7.14 (d, J=16.4 Hz, 1H), 7.14-7.15 (overlapping d, 2H), 7.36(d, J=16.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H), 7.54(t, J=3.1 Hz, 1H), 7.62 (dd, J=1.7, 8.1 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H),7.88 (d, J=8.4 Hz, 2H).

Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalenyl)ethenyl]benzoate(Compound A16)

To a degassed solution of 0.35 g (1.0 mmol) of 2-bromo-5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalene (Compound A35) and 0.34g (1.9 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine, wasadded 0.066 g (0.2 mmol) of tri-o-tolylphosphine and then 0.025 g (0.1mmol) of palladium(II) acetate. The reaction was heated at 90° C. for2.25 h. The reaction was concentrated in vacua. The residue was purifiedby flash chromatography (silica, 5% ethyl acetate in hexane), followedby recrystallization using EtOH to afford the title compound as whitecrystals.

¹H NMR (CDCl₃): δ 1.35 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.41 (d, J=4.7Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.55 (t, J=4.7 Hz, 1H), 6.93 (d, J=16.3Hz, 1H), 7.08-7.16 (m, 2H), 7.22-7.27 (m, 6H), 7.32 (d, J=8.2 Hz, 1H),7.38 (dd, J=1.7, 8.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.81 (d, J=1.7 Hz,1H), 8.00 (d, J=8.4 Hz, 2H).

Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]benzoate(Compound A17)

To a solution of 0.090 g (0.2 mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalenyl)ethenyl]benzoate(Compound A16) in 2.0 mL of methylene chloride was added dropwise asolution of 140 mg (0.45 mmol, 50-60%) of m-chloroperoxybenzoic acid in2.0 mL of methylene chloride and the reaction stirred at roomtemperature for 3.5 h. The mixture was diluted with water and extractedwith methylene chloride (2×). The organic phase was dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by flashchromatography (silica, 30% ethyl acetate in hexanes) followed byrecrystallization in EtOH to afford the title compound as a solid.

¹H NMR (CDCl₃): δ 1.22 (s, 6H), 1.42 (t, J=7.1 Hz, 3H), 2.50 (d, J=4.9Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.00 (d, J=16.4 Hz, 1H), 7.13 (d,J=16.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.40 (dd, J=1.7, 8.1 Hz, 1H),7.46-7.57 (m, 6H), 7.97 (m, 2H), 8.04 (d, J=8.4 Hz, 2H), 8.11 (d, J=1.7Hz, 1H).

(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]BenzoicAcid (Compound A18)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 60 mg (0.14mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]benzoate(Compound A16) was converted into the title compound (white solid).

¹H NMR (DMSO-D₆): δ 1.29 (s, 6H), 2.40 (d, J=4.6 Hz, 3H), 6.61 (t, J=4.6Hz, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.17-7.20 (m, 1H), 7.28-7.35 (m, 4H),7.38 (d, J=8.1 Hz, 1H), 7.52 (dd, J=1.6, 8.1 Hz, 1H), 7.67 (d, J=8.4 Hz,2H), 7.73 (d, J=1.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H).

(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]BenzoicAcid (Compound A19)

To a cold solution (0° C.) of 61 mg (0.15 mmol) of(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]benzoicacid (Compound A18) in 5.0 mL of methylene chloride and 2.0 mL oftetrahydrofuran was added dropwise a cold solution (0° C.) of 70 mg(0.22 mmol, 50-60%) of m-chloroperoxybenzoic acid in 4.0 mL of methylenechloride and the reaction stirred at 0° C. for 7 min. The mixture wasdiluted with water and extracted with methylene chloride (2×). Theorganic phase was dried over Na₂SO₄ and concentrated in vacuo.Recrystallization from acetonitrile gave the title compound as a solid.

¹H NMR (DMSO-D₆): δ 1.16 (s, 6H), 2.54 (d, J=4.6 Hz, 2H), 7.08 (d,J=16.4 Hz, 1H), 7.35-7.41 (m, 2H), 7.48 (t, J=4.6 Hz, 1H), 7.56 (d,J=8.7 Hz, 1H), 7.63-7.68 (m, 3H), 7.75 (d, J=8.2 Hz, 2H), 7.93-7.96 (m,3H), 8.03 (d, J=8.2 Hz, 2H).

Ethyl(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]benzoate(Compound A20)

To a degassed solution of 0.50 g (1.7 mmol) of2-bromo-5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalene (CompoundA36) and 0.45 g (2.5 mmol) of ethyl 4-vinylbenzoate in 4.0 mL oftriethylamine, was added 109 mg (0.36 mmol) of tri-o-tolylphosphine andthen 35 mg (0.16 mmol) of palladium(II) acetate. The reaction was heatedat 90° C. for 2.25 h. The reaction was concentrated in vacuo andpurified by flash chromatography (silica, 2% ethyl acetate in hexane) toafford the title a compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.29 (s, 6H), 1.30 (t, J=7.4 Hz, 3H), 1.41 (t, J=7.1Hz, 3H), 2.31 (d, J=4.8 Hz, 2H), 2.75 (q, J=7.4 Hz, 2H), 4.38 (q, J=7.1Hz, 2H), 6.20 (t, J=4.8 Hz, 1H), 7.12 (d, J=16.3 Hz, 1H), 7.24 (d,J=16.3 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.41 (dd, J=1.7, 8.0 Hz, 1H),7.57 (d, J=8.4 Hz, 2H), 7.89 (d, J=1.7 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H).

(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]BenzoicAcid (Compound A21)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 206 mg (0.52mmol) of ethyl(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]benzoate(Compound A20) was converted into the title compound (white solid).

1H NMR (DMSO-D₆): δ 1.22 (t, J=7.1 Hz, 3H), 1.23 (s, 6H), 2.27 (d, J=4.9Hz, 2H), 2.75 (q, J=7.1 Hz, 2H), 6.15 (t, J=4.9 Hz, 1H), 7.24 (d, J=16.4Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.75 (m, 3H),7.92 (d, J=8.1 Hz, 2H).

(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylsulfonyl)-naphthalen-2-yl)ethenyl]benzoate(Compound A22)

To a cold solution (0° C.) of 44 mg (0.12 mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]benzoicacid (Compound A21) in 4.0 mL of methylene chloride and 0.5 mL oftetrahydrofuran was added dropwise a cold solution (0° C.) of 55 mg(0.18 mmol, 50-60%) of m-chloroperoxybenzoic acid in 3.0 mL of methylenechloride and the reaction stirred at 0° C. for 30 min. The mixture wasdiluted with water and extracted with methylene chloride (2×). Theorganic phase was diluted with EtOAc, dried over Na₂SO₄ and thenconcentrated in vacuo. Recrystallization from acetonitrile gave thetitle compound as a solid.

¹H NMR (DMSO-D₆): δ 1.16 (t, J=7.3 Hz, 1H), 1.25 (s, 6H), 2.50 (d, J=4.8Hz, 2H), 3.32 (q, J=7.3 Hz, 2H), 7.18 (t, J=4.8 Hz, 1H), 7.25 (d, J=16.4Hz, 1H), 7.46 (d, J=16.4 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.71 (dd,J=1.5, 8.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 8.04(d, J=1.5 Hz, 1H).

Ethyl (E)-4-[-2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(1,3-dithian-2-yl)naphthalen-2-yl)ethenyl]benzoate (Compound A23)

To a cold solution (0° C.) of 140 mg (0.40 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2), in 6.0 mL of methylene chloride was added dropwise 130 mg(0.12 mL, 1.2 mmol) of 1,3-propanedithiol and 0.17 g (0.15 mL, 102 mmol)of borontrifluoride diethyl etherate. The reaction stirred between 0° C.and room temperature for 4 h. The mixture was diluted with aqueous sat.potassium carbonate, and extracted with ether (2×). The organic phasewas washed with brine, dried over MgSO₄ and then concentrated in vacuo.The crude product was purified by flash chromatography (silica, 10%ethyl acetate in hexane) to afford the title compound as a solid.

¹H NMR (CDCl₃): δ 1.29 (s, 6H), 1.39 (t, J=7.1 Hz, 3H), 1.83 (m, 2H),2.00 (m, 1H), 2.09 (m, 1H), 2.62 (m, 2H), 2.74 (m, 2H), 3.17 (m, 2H),4.36 (q, J=7.1 Hz, 2H), 7.09 (d, J=16.4 Hz, 1H), 7.20 (d, J=16.4 Hz,1H), 7.30 (d, J=8.2 Hz, 1H), 7.41 (dd, J=1.9, 8.2 Hz, 1H), 7.55 (d,J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 8.10 (d, J=1.9 Hz, 2H).

(E)-4-[2-(5,6.7.8-Tetrahydro-5,5-dimethyl-8-(2-(1,3-dithian-2-yl)naphthalenyl)ethenyl]-BenzoicAcid (Compound A24)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 81 mg (0.18mmol) of ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(1,3-dithian-2-yl)naphthalen-2-yl)ethenyl]benzoate (Compound A23) was converted into thetitle compound (white solid).

¹H NMR (CD₃OD): δ 1.28 (s, 6H), 1.83 (m, 2H), 1.93 (m, 1H), 2.19 (m,1H), 2.66 (m, 4H), 3.22 (m, 2H), 7.18 (d, J=16.4 Hz, 1H), 7.28 (d,J=16.4 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.48 (dd, J=1.9, 8.2 Hz, 1H),7.66 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 8.12 (d, J=1.9 Hz, 2H).

Ethyl(E)-4-[2-(5,6-tetrahydro-5,5-dimethyl-8-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A25)

To a degassed solution of 0.36 g (1.3 mmol) of 7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene (CompoundA37) and 0.44 g (2.5 mmol) of ethyl 4-vinylbenzoate in 3.6 g (5.0 mL, 36mmol) of triethylamine, was added 88 mg (0.29 mmol) oftri-o-tolylphosphine and then 33 mg (0.15 mmol) of palladium(II)acetate. The reaction was heated at 95° C. for 4 h. The reaction wasconcentrated in vacuo and purified by flash chromatography (silica, 1%ethyl acetate in hexane) to afford the title compound as an oil.

¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.39 (t, J=7.1 Hz, 3H), 1.64 (t, J=6.8Hz, 2H), 1.89 (s, 3H), 2.00 (s, 3H), 2.51 (t, J=6.8 Hz, 2H), 4.38 (q,J=7.1 Hz, 2H), 7.02 (d, J=16.4 Hz, 1H), 7.18-7.37 (overlapping d, 3H),7.41 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H).

(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(2)-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]-BenzoicAcid (Compound A26)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]benzoic acid (Compound A4) 95 mg (0.25mmol) of ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(methylethyliden-2-yl)naphthalen-2-yl)ethenyl]benzoate (Compound A25) was converted into thetitle compound using 1.0 mL (2.3 mmol) of LiOH (2.3 M aqueous solution).

¹H NMR (CDCl₃): δ 1.26 (s, 6H), 1.64 (t, J=6.9 Hz, 2H), 1.86 (s, 3H),2.02 (s, 3H), 2.53 (t, J=6.9 Hz, 2H), 7.07 (d, J=16.4 Hz, 1H), 7.22-7.38(overlapping d, 3H), 7.42 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 8.08 (d,J=8.4 Hz, 2H).

Ethyl(E)-4-[2-(7.8-dihydro-5,5-dimethyl-8(7H)-(pentyliden-3-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A27)

To a degassed solution of 0.30 g (0.98 mmol) of7-bromo-1(2H)-(pentyliden-3-yl)3,4-dihydro-4,4-dimethylnaphthalene(Compound A38) and 0.17 g (0.97 mmol) of ethyl 4-vinylbenzoate in 3.63 g(5.0 mL, 36 mmol) of triethylamine, was added 61 mg (0.2 mmol) oftri-o-tolylphosphine and then 23 mg (0.10 mmol) of palladium(II)acetate. The reaction was heated at 95° C. for 6.5 h. The reaction wasthen concentrated in vacuo and purified by flash chromatography (silica,100% hexane) followed by recrystallization from ethanol gave the titlecompound as white crystals.

¹H NMR (CDCl₃): δ 1.05 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.4 Hz, 3H), 1.24(s, 6H), 1.39 (t, J=7.2 Hz, 3H), 1.65 (t, J=6.8 Hz, 2H), 2.22 (q, J=7.4Hz, 2H), 2.31 (q, J=7.3 Hz, 2H), 2.50 (t, J=6.8 Hz, 2H), 4.36 (q, J=7.2Hz, 2H), 7.04 (d, J=16.4 Hz, 1H), 7.17 (d, J=16.4 Hz, 1H),7.28(d, J=8.1Hz, 1H),7.34 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 7.53 (d, J=8.4 Hz, 2H),8.00 (d, J=8.4 Hz, 2H).

(E)-4-[2-(5,6-Dihydro-5,5-dimethyl-8(7H)-(pentyliden-3-yl)-naphthalen-2-yl)ethenyl]BenzoicAcid (Compound A28)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 150 mg (0.37mmol) of ethyl(E)-4-[2-(5,6,-dihydro-5,5-dimethyl-8(7H)-(pentyliden-3-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A27) was converted into the title compound (white solid).

¹H NMR (Acetone-D₆): δ 1.08 (t, J=7.4 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H),1.26 (s, 6H), 1.67 (t, J=7.1 Hz, 3H), 2.25 (q, J=7.4 Hz, 2H), 2.33 (q,J=7.4 Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 7.13 (d, J=16.4 Hz, 1H), 7.28 (d,J=16.4 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.34 (m, 2H), 7.62 (d, J=8.4 Hz,2H), 7.98 (d, J=8.4 Hz, 2H).

Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(cyclohexylidenyl)naphthalen-2-yl)ethenyl]-benzoate(Compound A29)

To a degassed solution of 0.40 g (1.3 mmol) of 7-bromo-1(2H)-(cyclohexylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene (CompoundA39) and 0.62 g (3.5 mmol) of ethyl 4-vinylbenzoate in 2.2 g (3.0 mL, 22mmol) of triethylamine, was added 76 mg (0.25 mmol) oftri-o-tolylphosphine and then 29 mg (0.13 mmol) of palladium(II)acetate. The reaction was heated at 95° C. for 2.5 h. The reaction wasthen concentrated in vacuo and purified by flash chromatography (silica,1% ethyl acetate in hexane) to afford the title compound as a whitesolid.

¹H NMR (CDCl₃): δ 1.27 (s, 6H), 1.39 (t, J=7.1 Hz, 3H), 1.62 (m, 8H),2.34 (m, 2H), 2.53 (m, 4H), 4.37 (q, J=7.1 Hz, 2H), 7.04 (d, J=16.4 Hz,1H), 7.18 (d, J=16.4 Hz, 1H), 7.28-7.35 (m, 3H), 7.53 (d, J=8.4 Hz, 2H),8.01 (d, J=8.4 Hz, 2H).

(E)-4-[2-(5,6-Dihydro-5,5-dimethyl-8(7H)-(cyclohexylidenyl)-naphthalen-2-yl)ethenyl]BenzoicAcid (Compound A31)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 280 mg (0.68mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(cyclohexylidenyl)-naphthalen-2-yl)ethenyl]benzoate(Compound A29) was converted into the title compound using 2.0 mL (3.3mmol) of LiOH (1.7 M aqueous solution).

¹H NMR (DMSO-D₆): δ 1.28 (s, 6H), 1.59-1.67 (m, 8H), 2.36 (m, 2H),2.48-2.57 (m, 4H), 7.08 (d, J=16.3 Hz, 1H), 7.20-7.38 (m, 5H), 7.59 (d,J=8.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H).

(+/−) Ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(methylcarbethoxy)naphthalen-2-yl)ethenyl]benzoate(Compound A32)

To a refluxing solution of 0.75 g (11.5 mmol) of granular zinc in 5.0 mLof benzene was added a solution of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) in 5.0 mL of benzene followed by 0.27 g (0.18 mmol) ofethyl bromoacetate. The resulting mixture was refluxed for 24 h. Thereaction was cooled, filtered through celite. The filtrate was washedwith 10% HCl, sat. aqueous NaHCO₃ and brine. The organic phase was driedover Na₂SO₄ and concentrated in vacuo. The crude material was purifiedby flash chromatography (silica, 10% ethyl acetate in hexane) to affordthe title compound as a white solid.

¹H NMR (CDCl₃): δ 1.30 (t, J=7.1 Hz, 3H), 1.30 (3H, s), 1.34 (3H, s),1.41 (t, J=7.1 Hz, 3H), 1.77 (m, 2H), 2.09 (m, 2H), 2.82 (d, J=3.4 Hz,2H), 4.17 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 7.10(d, J=16.4 Hz, 1H), 7.20 (d, J=16.4 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H),7.42 (dd, J=1.9, 8.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.75 (d, J=1.9 Hz,1H), 8.03 (d, J=8.4 Hz, 2H).

Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(methylcarbethoxy)naphthalen-2-yl)ethenyl]benzoate(Compound A33a) Ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7)-anti(carbethoxymethylidenyl)-naphthalen-2-yl)ethenyl]benzoate (CompoundA33b)

To a solution of 0.25 g (0.57 mmol) of (+/−)ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(methylcarbethoxy)-naphthalen-2-yl)ethenyl]benzoate(Compound A32) in 11.0 mL of benzene was added 1.0 g (4.2 mmol) ofBurgess reagent and the resulting solution was heated at 55° C. for 30min. The reaction was cooled and concentrated in vacuo, the residue wasdiluted with water and extracted with EtOAc (2×), the organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo toafford a mixture of title compounds in a 3:1 ratio (endo:exo). The titlecompounds were seperated by flash chromatography (silica, 5% ethylacetate in hexane) to afford the pure isomers as white solids.

Compound A33a:

1H NMR (CDCl₃) δ 1.21 (t, J=7.1 Hz, 3H), 1.30 (s, 6H), 1.41 (t, J=7.1Hz, 3H), 2.82 (d, J=4.3 Hz, 2H), 3.51 (s, 2H), 4.12 (q, J=7.1 Hz, 2H),4.38 (q, J=7.1 Hz, 2H), 5.97 (t, J=4.3 Hz, 1H), 7.05 (d, J=16.4 Hz, 1H),7.19 (d, J=16.4 Hz, 1H), 7.30-7.40 (m, 3H), 7.47 (d, J=8.4 Hz, 2H), 8.03(d, J=8.4 Hz, 2H).

4,4-Dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35)

To a stirred solution of4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G, 1.48 g,5.9 mmol), titanium tetrachloride (1.09 g, 5.7 mmol) and THF (10 mL) wasadded a mixture of thiophenol (660 mg, 6 mmol), triethylamine (1.16 g,11.5 mmol) and THF (20 mL) via an addition funnel at ambienttemperature. The mixture was stirred for 5 h, and water (10 mL) wasadded, extracted with ether (3×50 mL). The combined organic layer waswashed successively with water (10 mL), 10% NaHCO₃ (10 mL) and brine (10mL). The organic layer was dried (MgSO₄) and the solvent distilled offat reduced pressure. After silicagel chromatography the title compoundwas obtained as a colorless oil.

1H NMR (CDCl₃): δ 1.31 (s, 6H), 2.39 (d, J=4.9 Hz, 2H), 6.54 (t, J=4.9Hz, 1H), 7.10-7.35 (m, 7H), 7.78 (d, J=2.0 Hz, 1H).

2-Bromo-5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalene (CompoundA36)

To a solution of 1.03 g (4.1 mmol) of7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) in30.0 mL of tetrahydrofuran, was added dropwise 0.49 g (0.85 mL, 7.8mmol) of titaniumtetrachloride and the resulting solution stirred for 10min. A solution of 35 mg (0.50 mL, 6.7 mmol) of ethanethiol and 0.54 g(0.75 mL, 5.4 mmol) of triethylamine in 10.0 mL of tetrahydrofuran wasadded and the reaction stirred at room temperature for 13 h. The mixturewas diluted with water and extracted with ether (2×). The organic phasewas washed with brine, dried over Na₂SO₄ and then concentrated in vacuo.Purification by flash chromatography (silica, 100 % hexane) gave thetitle compound as an oil.

¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.27 (t, J=7.1 Hz, 3H), 2.29 (d, J=4.8Hz, 2H), 2.70 (q, J=7.1 Hz, 2H), 6.23 (t, J=4.8 Hz, 1H), 7.17 (d, J=8.2Hz, 1H), 7.35 (dd, J=1.7, 8.2 Hz, 1H), 7.85 (d, J=2.1 Hz, 2H).

7-Bromo-1(2H)-(propyliden-2-yl)-3.4-dihydro-4.4-dimethylnaphthalene(Compound A37)

To a slurry of titanium trichloride (5 g, 32 mmol) in DME (80 mL) wasadded lithium wire in small portions (0.7 g, 100 mmol) under argonatmosphere. The mixture was refluxed for 1 h, cooled to ambienttemperature and a solution of acetone (928 mg, 16 mmol) and7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 1.0 g,3.96 mmol) in 20 mL of DME was added. The resultant mixture was refluxedfor 16 h under argon atmosphere. The reaction mixture was then cooled toambient temperature and diluted with hexane (100 mL), And thereafterfiltered through a pad of florisil. The filtrate was concentrated underreduced pressure and purified by flash chromatography (silica, 100%hexane) to afford the title compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.19 (s, 6H), 1.56 (t, J=6.9 Hz, 2H), 1.81 (s, 3H),1.94 (s, 3H), 2.44 (t, J=7.1 Hz, 2H), 7.11 (d, J=8.3 Hz, 1H), 7.23 (dd,J=2.1, 8.4 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H).

7-Bromo-1(2H)-(pentyliden-2-yl)-3,4-dihydro-4.4-dimethylnaphthalene(Compound A38)

Employing the same general procedure as for the preparation of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37), 1.0 g (3.97 mmol) of4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) wasconverted into the title compound using 1.37 g (15.9 mmol) of3-pentanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) oftitanium trichloride.

¹HNMR (CDCl₃): δ 1.04 (t, J=7.5 Hz, 3H), 1.14 (t, J=7.5 Hz, 3H), 1.23(s, 6H), 1.63 (t, J=7.1 Hz, 2H), 2.21 (q, J=7.5 Hz, 2H), 2.29 (q, J=7.5Hz, 2H), 2.49 (t, J=7.1 Hz, 2H), 7.15 (d, J=8.3 Hz, 1H), 7.29 (dd,J=2.2, 8.3 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H).

7-Bromo-1(2H)-(cyclohexylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A39)

Employing the same general procedure as for the preparation of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37), 1.0 g (3.97 mmol) of4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) wasconverted into the title compound using 1.56 g (15.9 mmol) ofcyclohexanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) oftitanium trichloride.

¹HMR (CDCl₃): δ 1.23 (s, 6H), 1.50-1.65 (m, 8H), 2.33 (br s, 2H), 2.45(t, J=5.5 Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H), 7.26(d, J=1.6 Hz, 1H), 7.29 (br s, 1H).

Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-naphth-7-yl]naphth-2-oate(Compound B1)

To a degassed solution of 0.39 g (1.4 mmol) of ethyl6-bromo-naphthalene-2-carboxylate and 3.0 mL of toluene, was addedsequentially 49 mg (0.04 mmol) of tetrakis-triphenylphosphinepalladium(0), 2.0 mL (2.0 mmol) of 1M sodium carbonate and then asolution of 0.32 g (1.6 mmol) of(5,6,7,8-tetrahydro-5,5-dimethylnaphth-2-yl)boronic acid (Compound B13)in 3.0 mL of MeOH. The reaction was heated at 80° C. for 6 h, dilutedwith 2N Na₂CO₃, and extracted with CH₂Cl₂ (2×), the organic layer waswashed with brine, dried over MgSO₄, and concentrated in vacuo to givean oil. Flash chromatography (silica, 5% ethyl acetate in hexane) of thecrude material gave the title compound as a white solid.

¹H NMR (CDCl₃, 300 MHz): δ_(—)1.35 (s, 6H), 1.46 (t, J=7.1 Hz, 3H),1.70-1.74 (m, 2H), 1.85-1.89 (m, 2H), 2.88 (t, J=6.3 Hz, 2H), 4.46 (q,J=7.1 Hz, 2H), 7.42 (d, J=1.7 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.52 (dd,J=2.0, 8.2 Hz, 1H), 7.80 (dd, J=1.7, 8.5 Hz, 1H), 7.91 (d, J=8.6 Hz,1H), 8.00 (d, J=8.5 Hz, 1H), 8.05 (s, 1H), 8.08 (dd, J=1.7, 8.6 Hz, 1H),8.61 (s, 1H).

6-[5,6,7,8-Tetrahydro-5,5-dimethyl-naphth-7-yl]-2-naphthoic Acid(Compound B2)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 50 mg (0.14mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-naphth-7-yl]naphth-2-oate(Compound B1) was converted into the title compound (white solid).

¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.28 (s, 6H), 1.64-1.68 (m, 2H),1.77-1.80 (m, 2H), 2.82 (t, J=5.7 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.49(s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.89 (dd J=1.8, 8.7 Hz, 1H), 7.98 (dd,J=1.8, 8.7 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 8.24(s, 1H), 8.60 (s, 1H).

Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-7-yl]naphth-2-oate(Compound B3)

To a degassed solution of 722 mg (2.6 mmol) of ethyl6-bromo-naphthalenecarboxylate in 6.0 mL of toluene, was addedsequentially 90 mg (0.08 mmol) of tetrakis-triphenylphosphine palladium(0), 5.0 mL (10.0 mmol) of 2M sodium carbonate, and a solution of 1.018g (3.1 mmol) of(5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)naphth-2-yl)boronicacid (Compound B14) in 3.0 mL of MeOH. The reaction was heated at 90° C.for 15 h. The reaction was diluted with 2N Na₂CO3, and extracted withCH₂Cl₂ (2×), the organic layer was washed with brine, dried over MgSO₄,and concentrated in vacuo to give an oil. The crude product was purifiedflash chromatography (silica, 5% ethyl acetate in hexane) to afford thetitle compound as a white solid.

¹H NMR (CDCl₃, 300 MHz): δ_(—)0.20 (s, 3H), 0.23 (s, 3H), 1.00 (s, 9H),1.35 (s, 6H), 1.46 (t, 3H, J=7.1 Hz), 1.70-2.10 (m, 4H), 4.46 (q, J=7.1Hz, 2H), 4.83 (dd, J=4.7, 8.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.60 (dd,J=2.1, 8.2 Hz, 1H), 7.79-7.82 (overlapping s, dd, 2H), 7.90 (d, J=8.7Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 8.06-8.1 (overlapping s, dd, 2H), 8.62(s, 1H).

Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]naphth-2-oate(Compound B4)

To a cold (0° C.) solution of 1.15 g (2.4 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-7-yl]naphth-2-oate(Compound B3) in 12.0 mL of tetrahydrofuran, was added 3.1 g (12.0 mL,12.0 mmol, 1.0 M in tetrahydrofuran) of tetrabutylammoniumfluoride andthe mixture was stirred between 0° C. to room temperature for 3 h. Thereaction was then concentrated in vacuo, diluted with water, andextracted with ether (2×), the organic layer was washed with brine,dried over MgSO₄, and concentrated in vacua to give a solid.Recrystallization from ethanol gave the title compound as a white solid.

¹H NMR (CDCl₃, 300 MHz): δ_(—)1.32 (s, 3H), 1.39 (s, 3H), 1.46 (t, J=7.1Hz, 3H), 1.66-1.72 (m, 1H), 1.90-1.99 (m, 3H), 2.11-2.20 (m, 1H), 4.47(q, J=7.1 Hz, 2H), 4.85 (t, J=5.0 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.63(dd, J=2.1, 8.2 Hz, 1H), 7.81 (dd, J=1.8, 8.7 Hz, 1H), 7.83 (s, 1H),7.90 (d, J=8.5 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 8.08 (overlapping, 2H),8.61 (s, 1H).

6-[5,6,7,8-Tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]-2-NaphthoicAcid (Compound B5)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 124 mg (0.33mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]naphth-2-oate(Compound B4) was converted into the title compound.

¹H NMR (DMSO, 300 MHz): δ_(—)1.25 (s, 3H), 1.29 (s, 3H), 1.58-1.99 (m,4H), 3.33 (s, 1H), 4.62 (s, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.66 (dd,J=2.0, 8.2 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.89 (dd J=1.7, 8.6 Hz, 1H),8.00 (dd, J=1.7, 8.6 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 8.19 (d, J=8.6 Hz,1H), 8.24 (s, 1H), 8.61 (s, 1H).

Ethyl-6-[5,5-dimethyl-5,6-dihydro-naphthlen-8(7H)-one-2-yl]-naphthalen-2-oate(Compound B6)

To a solution of 101 mg (0.27 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]naphth-2-oate(Compound B4) in 1.5 mL of methylene chloride was added 50 mg (0.43mmol) of N-methylmorpholine N-oxide and 6.0 mg (0.017 mmol) oftetrapropylammonium perruthenate(VII). The reaction was stirred at roomtemperature for 3 h, diluted with water, and extracted with CH₂Cl₂ (2×).The combined organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo to give a foam. The title compound was obtained asa white solid after flash chromatography (silica, 10% ethyl acetate inhexane).

¹H NMR (CDCl₃, 300 MHz): δ 1.46 (overlapping s, 6H), 1.46 (overlappingt, J=7.1 Hz, 3H), 2.09 (t, J=6.4 Hz, Z H), 2.80 (t, J=6.4 Hz, 2H), 4.46(q, J=7.1 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.83 (dd, J=1.8, 8.6 Hz, 1H),7.90-7.95 (several d, 2H), 8.04 (d, J=8.4 Hz, 1H), 8.09-8.12(overlapping s, dd, 2H), 8.41 (d, J=2.1 Hz, 1H), 8.63 (s, 1H).

6-[5,5-Dimethyl-5,6-dihydro-naphthlen-8(7H)-one-2-yl]-2-Naphthoic Acid(Compound B7)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoic acid (Compound A4) 58 mg (0.16mmol) of ethyl-6-[5,5-dimethyl-5,6-dihydro-naphthlen-8(7H)-one-2-yl]-naphthalen-2-oate(Compound B6) was converted into the title compound (white solid).

¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.41 (s, 6H), 2.01 (t, J=6.7 Hz, 2H),2.74 (t, J=6.7 Hz, 2H), 7.71 (d, J=8.3 Hz, 1H), 7.93 (dd, J=1.8, 8.7 Hz,1H), 7.93 (dd, J=1.7, 8.5 Hz, 1H), 8.07-8.13 (several d, 3H), 8.22 (d,J=8.5 Hz, 1H), 8.26 (s, 2H), 8.32 (s, 1H), 8.63 (s, 1H).

Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-7-yl]naphth-2-oate(Compound B8)

To a cold (0° C.) solution of 130 mg (0.35 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(hydroxy)-naphth-7-yl]naphth-2-oate(Compound B4) in 2.0 mL of methylene chloride was added 50 mg (0.15 mL,0.86 mmol) of Hunig's base, followed by 0.21 g (0.20 mL, 2.6 mmol)chloromethyl methyl ether was added and stirred at room temperature for14 h. About 500 mgs of t-butylammonium iodide was then added and thereaction was warmed to 35° C. for one additional hour. The reaction wasdiluted with water, and extracted with CH₂Cl₂ (2×). The combined organiclayer was washed with brine, dried over MgSO₄, and concentrated in vacuoto give an oil. The title compound was obtained as an oil after flashchromatography (silica, 10% ethyl acetate).

¹H NMR (CDCl₃, 300 MHz): δ_(—)1.31 (s, 3H), 1.40 (s, 3H), 1.46 (t, 3H,J=7.1 Hz), 1.60 (m, 1H), 1.98-2.08 (m, 3H), 3.51 (s, 3H), 4.46 (q, J=7.1Hz, 2H), 4.75 (t, J=4.5 Hz, 1H), 4.83 (d, J=7.0 Hz, 1H), 4.93 (d, J=7.0Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.63 (dd, J=2.0, 8.2 Hz, 1H), 7.70 (d,J=2.0 Hz, 1H), 7.80 (dd J=1.7, 8.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 8.01(d, J=8.7 Hz, 1H), 8.05 (s, 1H), 8.09 (dd, J=1.7, 8.7 Hz, 1H), 8.62 (s,1H).

6-[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-7-yl]-2-NaphthoicAcid (Compound B9)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoic acid (Compound A4) 90 mg (0.21mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-7-yl]naphth-2-oate(Compound B8) was converted into the title compound (white solid).

¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.26 (s, 3H), 1.34 (s, 3H), 1.59 (m,1H), 1.98 (m, 3H), 3.34 (s, 3H), 4.68 (t, J=4.5 Hz, 1H), 4.78 (d, J=6.8Hz, 1H), 4.84 (d, J=6.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.70 (s, 1H),7.73 (d, J=8.3 Hz, 1H), 7.90 (d J=8.7 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H),8.09 (d, J=8.7 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 8.24(s, 1H), 8.63 (s,1H).

Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(O-acetyl)-naphth-7-yl]naphth-2-oate(Compound B10)

To a cold (0° C.) solution of 61 mg (0.16 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy)-naphth-7-yl]naphth-2-oate(Compound B4) in 2.0 mL of methylene chloride stirring under argon at 0°C. was added successively, 76 mg (0.10 mL, 0.72 mmol) of triethylamine,0.22 g (0.20 mL, 2.8 mmol) of acetylchloride and 7 mg (0.06 mmol) of4-dimethylaminopyridine. The reaction was stirred at room temperaturefor 90 h, diluted with water, and extracted with CH₂Cl₂ (2×). Thecombined organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The title compound was obtained as an oil afterflash chromatography using silica, 10% ethyl acetate in hexane.

¹H NMR (CDCl₃, 300 MHz): δ_(—)1.31 (s, 3H), 1.43 (s, 3H), 1.46 (t, 3H,J=7.1 Hz), 1.67-1.72 (m, 1H), 1.94-2.12 (m, 3H), 2.12 (s, 3H), 4.46 (q,J=7.1 Hz, 2H), 6.06 (t, J=4.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.61 (d,J=2.0 Hz, 1H), 7.67 (dd, J=2.0, 8.2 Hz, 1H), 7.78 (dd J=1.7, 8.6 Hz,1H), 7.93 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 8.04 (s, 1H), 8.09(dd, J=1.7, 8.7 Hz, 1H), 8.62 (s, 1H).

Ethyl-6-[5,5-dimethyl-5,6-dihydro-naphthlen-8(7H)M-anti-(O-methyl-oxime)-2yl]-naphthalen-2-oate(Compound B11)

A solution of 29 mg (0.08 mmol) ofethyl-6-[5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl]-naphthalen-2-oate (Compound B6), 27 mg (0.32 mmol) ofmethoxylamine hydrochloride and 68 mg (0.5 mmol) of sodium acetate in2.0 mL of EtOH and 0.5 mL of tetrahydrofuran was heated at 50° C. for 18h. An additional 27 mg of methoxylamine hydrochloride was added and themixture refluxed for another 2 h. The mixture was concentrated in vacuo.The residue was diluted with water and extracted with EtOAc (2×). Thecombined organic layer was dried over MgSO₄, and concentrated in vacuo.Flash chromatography (silica, 5% ethyl acetate in hexanes) of the crudematerial afforded the title compound as a solid.

¹H NMR (CDCl₃, 300 MHz): δ_(—)1.35 (s, 6H), 1.46 (t, J=7.1 Hz, 3H), 1.77(t, J=6.9 Hz, 2H), 2.84 (t, J=6.9 Hz, 2H), 4.04 (s, 3H), 4.45 (q, J=7.1Hz, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.67 (dd, J=2.1, 8.2 Hz, 1H), 7.83 (dd,J=1.8, 8.5 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H),8.07-8.10 (m, 2H), 8.34 (d, J=2.1 Hz, 1H), 8.63 (s, 1H).

6-[5,5-Dimethyl-5,6-dihydro--naphthlen-8(7H-anti-(O-methyl-oxime)-2-yl]-2-NaphthoicAcid (Compound B12)

Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoicacid (Compound A4) 22 mg (0.06 mmol) of ethyl-6-[5,5-dimethyl-5,6-dihydro--naphthlen-8(7H)anti-(O-methyl-oxime)-2-yl]-naphthalen-2-oate(Compound B11) was converted into the title compound (white solid).

¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.30 (s, 6H), _(—)1.72 (t, J=6.9 Hz,3H), 2.78 (t, J=6.9 Hz, 2H), 3.97 (s, 3H), 7.59 (d, J=8.2 Hz, 1H), 7.81(dd, J=2.1, 8.2 Hz, 1H), 7.89 (dd, J=1.8, 8.7 Hz, 1H), 8.00 (dd, J=1.7,8.6 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.21-8.26 (m, 3H), 8.64 (s, 1H).

(5,6,7,8-Tetrahydro-5,5-dimethylnaphth-2-yl)Boronic Acid (Compound B13)

To a cold (−78° C.) solution of 2.02 g (8.4 mmol) of,6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene in 11.0 mL oftoluene, was added 4.6 g (6.8 mL, 10.9 mmol, 1.6 M in hexane) of n-BuLi.The resulting solution was stirred at −78° C. for 45 min. and then 2.40g (3.0 mL, 12.7 mmol) of triisopropylborate was dropwise added and thereaction stirred at room temperature for 12 h. The reaction was thendiluted with 10% HCl, and extracted with ether (2×). The combinedorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo to give an oil. Recrystallization from hexane afforded thetitle compound as a white solid.

¹H NMR (CDCl₃, 300 MHz): δ_(—)1.34 (s, 6H), 1.71 (m, 2H), 87 (m, 2H),1.89 (t, J=6.3 Hz, 2H), 7.47 (d, J=7.8 Hz, 1H), 7.89 (s, 1H), 7.99 (d,J=7.8 Hz, 1H).

(5,5-Dimethyl-8-(t-butyldimethylsilylloxy)-5,6,7,8-tetrahydro-naphth-2-yl)BoronicAcid (Compound B14)

Employing the same general procedure as for the preparation of1,2,3,4-tetrahydro-1,1-dimethylnaphthyl-6-boronic acid (Compound B13)12.40 g (34 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-(t-butyldimethylsilyloxy)naphthalene(Compound B15) was converted into the title compound using 18.4 g (27.0mL, 43 mmol, 1.6 M in hexane) of n-BuLi and 9.37 g (11.50 mL, 50 mmol)of trisiopropylborate.

¹H NMR (CDCl_(3, 300) MHz): δ_(—)0.22 (s, 3H), 0.28 (s, 3H), 0.98 (s,9H), 1.33 (s, 3H), 1.38 (s, 3H), 1.62-2.09 (m, 4H), 4.87 (m, 1H), 7.39(d, J=7.8 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.29 (s, 1H).

2-(5,6,7,8-tetrahydro-5,5-dimethy-8-(t-butyldimethylsilyloxy)naphthyl)bromide(Compound B15)

To a solution of 10.61 g (42 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene in 100 mLof methylene chloride stirring at 0° C. under argon, was added 5.23 g(7.20 mL, 52 mmol) of triethylamine, 0.55 g (4.5 mmol) of4-dimethylaminopyridine, and 7.71 g (51 mmol) of t-butyldimethylsilylchloride consecutively. The resulting solution was stirred at 0° C. toroom temperature for 90 hours. The reaction was then diluted with water,and extracted with methylene chloride (2×), the organic layers driedover Na₂SO₄, and concentrated in vacuo to give an oil. Purification wasdone using flash chromatography (silica, 4% ethyl acetate in hexane) togive the title compound as an oil.

¹H NMR (CDCl₃, 300 MHz): δ 0.15 (s, 3H), 0.18 (s, 3H), 0.95 (s, 9H),1.25 (s, 3H), 1.26 (s, 3H), 1.61-2.03 (m, 4H), 4.67 (m, 1H), 7.13 (d,J=8.5 Hz, 1H), 7.30 (dd, J=2.1, 8.5 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H).

4,4-Dimethyl-7-acetyl-3,4-dihydronaphthalen-1(2H)-one (Compound C1)

A solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one(Compound G) (1.78 g, 7 mmol), 1-ethoxyvinyltributyltin (EVTB) (3.3 g,9.12 mmol), bis(triphenylphosphine)palladium(II)chloride (260 mg, 0.23mmol) in THF (25 mL) was refluxed for 24 h under argon atmosphere. Tothe reaction, additional EVTB (1.5 g, 4.1 mmol) andbis(triphenylphosphine)palladium(II)chloride (200 mg, 0.2 mmol) wereadded and the mixture was and refluxed for an additional 24 h. Thereaction mixture was cooled to room temperature and 10% hydrochloricacid (10 ml) was added. After 10 min, the mixture was extracted withether (3×50 mL), the combined organic layer was washed with water (10mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried with magnesiumsulfate. Solvent was removed under reduced pressure, and afterpurification by flash chromatography the title compound was obtained asa white solid.

¹H NMR (CDCl₃): δ 1.38 (s, 6H), 2.02 (t, J=6.54 Hz, 2H), 2.73 (t, J=6.54Hz, 2H), 7.31 (d, J=8.43 Hz, 1H), 7.63 (dd, J=2.20, 8.43 Hz, 1H), 8.13(d, J=2.20 Hz, 1H).

Ethyl 3-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]but-2(E)-enoate (Compound C2)

To a cold (−78° C.) slurry of sodiumhydride (336 mg, 14 mmol) in THF (10mL) was added triethylphosphonoacetate (3.58 g, 16 mmol). Cooling wasdiscontinued and the mixture was stirred at ambient temperature. After30 min, a solution of4,4-dimethyl-7-acetyl-1,2,3,4-tetrahydronaphthalen-1(2H)-one (CompoundC1, 800 mg, 3.7 mmol) in THF (4 mL) was added and stirred for 36 h. Thereaction mixture was diluted with ether (120 mL), and washed with water(10 mL), brine (10 mL), dried with magnesium sulfate. Solvent wasremoved under reduced pressure, chromatographic purification gave thetitle compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.33 (t, J=7.1 Hz, 3H), 1.41 (s, 6H), 2.04 (t, J=7.0Hz, 2H), 2.59 (s, 3H), 2.76 (t, J=7.0 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H),6.19 (s, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.65 (dd, J=2.0, 8.3 Hz, 1H), 8.15(d, J=2.0 Hz, 1H).

3-[1-Hydroxy-4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-7-yl]but-2(E)-en-1-ol(Compound C3)

To a cold (−78° C.) solution of ethyl3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-enoate(Compound C2, 2.7 g, 9.4 mmol) in methylenechloride (20 mL) was addeddiisobutylaluminum hydride (DibAl-H, 1M solution in methylenechloride)(45 mL). The reaction was gradually warmed to −10° C. The reaction wasquenched by adding methanol (3 mL), water (10 mL), 10% hydrochoric acid(40 mL) and stirred for 10 min. The mixture was extracted withmethylenechloride (3×50 mL). The combined organic layer was washed withwater (10 mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried withmagnesium sulfate. Solvent was removed under reduced pressure to obtainthe title compound as a white solid.

¹HNMR (CDCl₃): d 1.24 (s, 3H), 1.31 (s, 3H), 1.57-1.70 (m, 2H),1.82-1.96 (m, 2H), 2.03 (s, 3H), 4.29 (d, J=6.6 Hz, 2H), 4.68 (brs, 1H),5.95 (t, J=6.6 Hz, 1H), 7.28 (brs, 2H), 7.48 (s, 1H).

3-[4,4-Dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]but-2(E)-en-al(Compound C4)

To a solution of3-[1-hydroxy-4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-7-yl]but-2(E)-en-1-ol(Compound C3, 1.5 g, 6.1 mmol) in dichloromethane (35 mL) was addedmanganese dioxide (9 g, 106 mmol) in two portions and stirred at roomtemperature for 48 h. After filtering out the manganese dioxide andremoving the solvent under reduced pressure the product was isolated asa white solid.

¹H NMR (CDCl₃): δ 1.41 (s, 6H), 2.03 (t, J=6.4 Hz, 2H), 2.58 (s, 3H),2.75 (t, J=6.4 Hz, 21), 6.41 (d, J=7.7 Hz, 1H), 7.48 (d, J=8.31, 1H),7.71 (dd, J=2.2, 8.31 Hz, 1H), 8.20 (d, J=2.2 Hz), 10.18 (d, J=7.7 Hz,1H).

Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C5)

To a cold (−78° C.) solution ofdiethyl-(E)-3-ethoxycarbonyl-2-methylallylphosphonate in THF was addedn-BuLi (1.6 mmol solution in hexanes, 2.2 mL, 3.5 mmol) followed by3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-en-al(Compound C4, 300 mg, 1.24 mmol) in THF (2 mL). The a mixture wasstirred for 16 h at −78° C. The mixture was treated with water andextracted with ether (3×40 mL). The combined organic layer was washedwith water (10 mL), brine (10 mL) and dried with MgSO₄. Solvent wasremoved under reduced pressure, the crude product was purified by columnchromatography, followed by HPLC to give the title compound as a solid.

¹H NMR (CDCl₃): δ 1.30 (t, J=7.1 Hz, 3H), 1.40 (s, 6H), 2.03 (t, J=6.8Hz, 2H), 2.26 (s, 3H), 2.38 (s, 3H), 2.75 (t, J=6.8 Hz, 2H), 4.20 (q,J=7.1 Hz, 2H), 5.82 (s, 1H), 6.41 (s, J=15.0 Hz, 1H), 6.64 (d, J=11.0Hz, 1H), 7.01 (dd, J=11.0, 15.0 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.66(dd, J=2.0, 8.2 Hz, 1H), 8.14 (d, J=2.0 Hz).

4,4-Dimethyl-7-acetyl-1-phenylthio-3,4-dihydronaphthalene (Compound C7)

Employing the procedure used for the preparation of4,4-dimethyl-7-acetyl-3,4-dihydronaphthalen-1(2H)-one (Compound C1) 1.2g, (3.5 mmol) of4,4-dimethyl-7-Bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35)was converted to the title compound.

¹H NMR (CDCl₃): δ 1.35 (s, 6H), 2.42 (d, J=4.8 Hz, 2H), 2.43 (s, 3H),6.59 (t, J=4.8 Hz, 1H), 7.10-7.27 (m, 4H), 7.32 (d, J=8.5 Hz, 1H), 7.40(d, J=8.1 Hz, 1H), 7.82 (dd, J=1.9, 8.1 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H).

3-[4,4-Dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-nitrile(Compound C8)

Employing the procedure used for the preparation of ethyl3-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]but-2(E)-enoate(Compound C2) instead using diethylcyanomethylphosphonate (1.77 g, 10mmol), sodium hydride (220 mg, 9 mmol) and4,4-dimethyl-7-acetyl-1-phenylthio-3,4-dihydronaphthalene (Compound C7,924 mg, 3 mmol) was converted to the title compound.

¹H NMR (CDCl₃) δ 1.34 (s, 6H), 2.30 (s, 3H), 2.42 (d, J=4.6 Hz, 2H),5.38 (s, 1H), 6.61 (t, J=4.6 Hz, 1H), 7.10-7.37 (m, 7H), 7.69 (d, J=1.9Hz, 1H).

3-[4,4-Dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-aldehyde(Compound C9)

To a cold (−78° C.) solution of3-[4,4-dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-nitrile(Compound C8, 400 mg, 1.2 mmol), in dichloromethane (10 mL) was addeddiisobutylaluminum hydride (DiBAl-H) (1M solution in dichloromethane,2.5 mL, 2.5 mmol). The reaction was warmed to −40° C. gradually over aperiod of 1 h. Then the reaction was quenched by adding methanol (1.5mL), diluted with ether: ethylacetate (1:1, 100 mL), washed with 10% HCl(10 mL), water (10 mL), and brine (10 mL). The organic layer was dried(MgSO₄) and the solvent was removed under reduced pressure. The titlecompound was obtained as a colorless oil after silicagel chromatography.

¹H NMR (CDCL₃): δ 1.36 (s, 6H), 2.40 (d, J=1.3 Hz, 3H), 2.42 (d, J=4.7Hz, 2H), 6.25 (dd, J=1.3, 7.9 Hz, 1H), 6.60 (t, J=4.7 Hz, 1H), 7.10-7.43(m, 7H), 7.81 (d, J=1.9 Hz, 1H), 10.11 (d, J=7.9 Hz, 1H).

Ethyl7-[4,4-dimethyl-1-(phenylthio)-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C10)

Employing the procedure used for the preparation of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C5) instead usingdiethyl-(E)-3-ethoxycarbonyl-2-methylallylphosphonate (786 mg, 3 mmol),n-BuLi (2.8 mmol),3-[4,4-dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-aldehyde(Compound C9, 280 mg, 0.84 mmol) was converted to the title compound.

¹H NMR (CDCl₃): δ 1.32 (t, J=7.1 Hz, 3H), 1.36 (s, 6H), 2.12 (s, 3H),2.38 (s, 3H), 2.41 (d, J=4.7 Hz, 2H), 4.20 (q, J=7.1 Hz, 2H), 5.82 (s,1H), 6.29 (d, J=14.8 Hz, 1H), 6.33 (d, J=9.9 Hz, 1H), 6.58 (t, J=4.7 Hz,1H), 6.96 (dd, J=9.9, 14.8 Hz, 1H), 7.12-7.38 (m, 7H), 7.74 (d, J=1.7Hz, 1H).

Ethyl7-[4,4-dimethyl-1-phenylsulfonyl-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C11a) Ethyl7-[4,4-dimethyl-1-phenylsulfoxide-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C11b)

To a cold (0° C.) solution of ethyl7-[4,4-dimethyl-1-phenylthio-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C10, 44 mg, 0.1 mmol) in dichloromethane (3 mL)was added m-chloroperoxybenzoic acid (approximately 60% concentration,30 mg, 0.1 mmol). The mixture was stirred for 2 h at 0° C., diluted withdichloromethane (40 mL) and washed successively with 10%sodiumbicarbonate (5 mL), water (5 mL) and brine (5 mL). The organiclayer was dried (MgSO₄) and the solvent was removed under reducedpressure. The title compounds were obtained after separation of themixture by silicagel chromatography.

Ethyl7-[4,4-dimethyl-1-phenylsulfonyl-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound 11a)

¹H NMR (CDCl₃): δ 1.23 (s, 6H), 1.31 (t, J=7.1 Hz, 3H), 2.17 (s, 3H),2.39 (s, 3H), 2.51 (d, J=4.9 Hz, 2H), 4.20 (q, J=7.1 Hz, 2H), 5.84 (s,1H), 6.36 (d, J=15.1 Hz, 1H), 6.41 (d, J=13.0 Hz, 1H), 6.99 (dd, J=12.0,15.1 Hz), 1H), 7.27 (d, J=1.7 Hz, 1H), 7.34 (dd, J=1.9, 8.2 Hz, 1H),7.45-7.60 (m, 4H), 7.93-8.0 (m, 3H).

Ethyl7-[4,4-dimethyl-1-phenylsulfoxide-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound 11b)

¹H NMR (CDCl₃): δ 1.32 (s, 3H), 1.30 (s, 3H), 1.31 (t, J=7.1 Hz, 3H),2.15 (s, 3H), 2.38 (s, 3H), 2.50 (d, J=4.6 Hz, 2H), 4.19 (q, J=7.1 Hz,2H), 5.84 (s, 1H), 6.36 (d, J=15.0 Hz, 1H), 6.39 (d, J=11.6 Hz, 1H),6.90-7.04 (m, 2H), 7.24-7.32 (m, 2H), 7.41-7.50 (m 3H), 7.53 (d, J=1.8Hz, 1H), 7.74 (dd, J=2.5, 8.0 Hz, 2H).

Ethyl7-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C13)

To cold (0° C.) solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C5, 6 mg, 0.02 mmol) in ether (3 mL) was addedZnBH₄ (0.5 M solution in ether, 0.5 mL). The mixture was stirred for 30min. and quenched the with water, diluted with is ether (30 mL). Theorganic layer was washed with water (5 mL), 10% HCl (5 mL), water (5mL), 10% NaHCO₃ (5 mL) and brine (5 mL). The organic layer was driedwith MgSO₄, and the solvent was removed under reduced pressure to obtainthe title compound as a white solid.

¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.34 (s, 3H),1.58-1.70 (m, 1H), 1.82-1.95 (m, 2H), 2.05-2.15 (m, 1H), 2.25 (s, 3H),2.38 (s, 3H), 4.18 (q, J=7.1 Hz), 4.75 (brs, 1H), 5.81 (s, 1H), 6.37 (d,J=15.1 Hz, 1H), 6.60 (d, J=11.2 Hz, 1H), 7.02 (dd, J=11.2, 15.1 Hz, 1H),7.31 (d, J=8.3 Hz, 1H), 7.39 (dd, J=2.1, 8.3 Hz, 1H).

Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C14)

To a cold (−78° C.) stirring solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C5, 190 mg, 0.55 mmol), in THF (10 mL) wasadded sodium bis(trimethylsilyl)amide (1M solution in THF, 0.5 mL, 0.5mmol). After 20 min.2-N,N-bis(trifluoromethylsulfonyl)amino-5-chloropyridine (216 mg, 0.6mmol) in THF (2 mL) was added, after another 20 min. the temparature wasincreased to −10° C. and the mixture was stirred at this temperature foranother 20 min. The reaction was quenched by adding aqueous NH₄Cl (10mL), extracted with ether (3×30 mL). The combined organic layer waswashed successively with water (10 mL) and brine (10 mL), dried withMgSO₄. The solvent was removed, and the resulting crude mixture waspurified by silicagel chromatography and HPLC to afford the titlecompound as a white solid.

¹H NMR (CDCl₃): δ 1.31 (t, J=7.1 Hz, 3H), 1.32 (s, 6H), 2.25 (s, 3H),2.39 (s, 3H), 2.43 (d, J=4.9, 2H), 4.19 (q, J=7.1 Hz, 2H), 5.83 (s, 1H),5.99 (t, J=4.9 Hz, 1H), 6.40 (d, J=15.0 Hz, 1H), 6.57 (d, J=11.3 Hz,1H), 7.01 (dd, J=11.3, 15.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.46 (dd,J=1.9, 8.0 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H).

Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C15)

To a cold (−78° C.) solution of thiophene (252 mg, 3 mmol) in THF (2 mL)was added t-BuLi (1.4 M solution in cyclohexane, 2 mL, 2.8 mmol) and themixture was warmed to −30° C. over a period of 30 min. The mixture wasrecooled to −78° C. and a solution of zinc chloride (408 mg, 3 mmol) inTHF (1 mL) was added to it. The white turbid mixture was warmed toambient temperature and stirred for 30 min. This mixture was transferredto a flask containing ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C14, 118 mg, 0.25 mmol), palladiumtetrakis(triphenylphosphine) (250 mg, 0.22 mmol) and THF (1 mL). Thereactants were heated to 50° C. for 3 h. and then the reaction wasquenched by adding aqueous NH₄Cl (10 mL). The reaction mixture wasextracted with ethylacetate (3×20 mL). The combined organic layer waswashed with water (10 mL) and brine (10 mL), dried with MgSO₄. Thesolvent was removed under reduced pressure and the title compound wasobtained as pale yellow solid after silicagel chromatography.

¹H NMR (CDCl₃): δ 1.29 (t, J=7.1 Hz), 1.33 (s, 6H), 2.18 (s, 3H), 2.33(d, J=4.8 Hz, 2H), 2.36 (s, 3H), 4.17 (q, J=7.1 Hz, 2H), 5.79 (s, 1H),6.21 (t, J=4.8 Hz, 1H) 6.33 (d, J=15.1 Hz, 1H), 6.48 (d, J=11.5 Hz, 1H),6.98 (dd, J=11.5, 15.1 Hz, 1H), 7.08 (br d, J=3,4 Hz, 2H), 7.26-7.29 (m,1H), 7.32-7.41 (m, 2H), 7.52 (d, J=1.6 Hz, 1H).

Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(anti)(O-methyl-oxime)-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C16)

To a solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C5, 25 mg, 0.07 mmol) in ethanol (2 mL) and THF (2 mL), wasadded sodium acetate trihydrate (103 mg, 0.75 mmol) followed bymethoxylamine hydrochloride (42 mg, 0.5 mmol). The mixture was stirredat ambient temperature for 16 h and diluted with ether (60 mL). Theether layer was washed successively with 10% NaHCO₃ (5 mL), water (5 mL)and brine (10 mL). The organic layer was dried with MgSO₄ and thesolvent was removed under reduced pressure. After purification bychromatography on silicagel the title compound was obtained as a whitesolid.

1H NMR (CDCl₃): δ 1.29 (s, 6H), 1.30 (t, J=7.1 Hz, 3H), 1.72 (t, J=7.0Hz, 2H), 2.27 (s, 3H), 2.39 (s, 3H), 2.80 (t, J=7.0 Hz, 2H), 4.03 (s,3H), 4.18 (q, J=7.1 Hz, 2H), 5.82 (s, 1H), 6.40 (d, J=15.0 Hz, 1H), 6.60(2, J=11.0 Hz, 1H), 7.03 (dd, J=11.0, 15.0 Hz, 1H), 7.33 (d, J=8.3 Hz,1H), 7.44 (dd, J=2.1 Hz, 8.3 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H).

Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(anti)(carbethoxymethylenyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C17a) Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(syn)(carbethoxyrethylenyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C17b)

To a cold (−78° C.) slurry of sodium hydride (24 mg, 1 mmol) in THF (3mL) was added triethylphosphonoacetate (300 mg, 1.4 mmol). The mixturewas stirred for 30 min. at 0° C. To this mixture a solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)-trienoate(Compound C5, 50 mg, 0.15 mmol) in THF (2 mL) was added and stirred atambient temperature for 48 h. The reaction was quenched by adding water(5 mL) and extracted with ethyl acetate (3×30 mL). The combined organiclayer was washed with water (5 mL), brine (5 mL) and dried (MgSO₄). Thesolvent was removed under reduced pressure and the title compounds wereobtained after silicagel chromatography and HPLC separation. Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(anti)(carbethoxymethylenyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate(Compound 17a)

¹H NMR (CDCl₃): δ 1.30 (s, 6H), 1.30 (t, J=7.1 Hz, 3), 1.34 (t, J=7.1Hz, 3H), 1.73 (t, J=6.6 Hz, 2H), 2.26 (s, 3H), 2.38 (s, 3H), 3.24 (t,J=6.6 Hz, 2H), 4.13-4.28 (m, 4H), 5.82 (s, 1H), 6.31 (s, 1H), 6.40 (d,J=15.0 Hz, 1H), 6.57 (d, J=11.5 Hz, 1H),7.01 (dd, J=11.5, 15.0 Hz, 1H),7.35 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.9, 8.3 Hz, 1H), 7.66 (d, J=1.9 Hz,1H).

Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(syn)(carbethoxymethylenyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C17b)

¹H NMR (CDCl₃): δ 1.25 (t, J=7.1 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.32(s, 6H), 1.83 (t, J=6.5 Hz, 2H), 2.23 (s, 3H), 2.38 (s, 3H), 2.54 (t,J=6.5 Hz, 2H), 4.12-4.25 (m, 4H), 5.81 (s, 2H), 6.38 (d, J=15.1 Hz, 1H),6.57 (d, J=11.0 Hz, 1H), 7.01 (dd, J=11.0, 15.1 Hz, 1H), 7.30 (d, J=8.3Hz, 1H), 7.46 (dd, J=1.9, 8.3 Hz, 1H), 7.72 (d, J=1.9 Hz, 1H).

7-[4,4-Dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoicacid (Compound C19)

To a solution of ethyl7-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C13, 35 mg, 0.1 mmol) in THF (3 mL) and methanol(1 mL), was added lithiumhydroxide (1M solution in water, 0.3 mL, 0.3mmol) and warmed to 60° C. for 6 h. The reaction mixture was dilutedwith ether : ethylacetate (1:1, 40 mL), acidified with 10% aqueous HClto pH 6. The organic layer was washed with water (5 mL), brine (5 mL)and dried (MgSO4), and the solvent was removed under reduced pressure.After purification by preparative TLC the title compound was obtained asa pale yellow solid.

1H NMR (CDCl₃): δ 1.26 (s, 3H), 1.34 (s, 3H), 1.55-1.65 (m, 1H),1.70-2.10 (m, 3H), 2.27 (s, 3H), 2.40 (s, 3H), 4.77 (t, J=5.6 Hz, 1H),5.84 (s, 1H), 6.41 (d, J=15.1 Hz, 1H), 6.62 (d, J=11.1 Hz, 1H), 7.08(dd, J=11.1, 15.1 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.40 (dd, J=1.9, 8.3Hz, 1H), 7.57 (d, J=1.9 Hz, 1H).

7-[4,4-Dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoicacid (Compound C20)

Employing the procedure used for the preparation of7-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoicacid (Compound C19), 20 mg (0.05 mmol) of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C15) was converted to the title compound.

¹H NMR (CD₃COCD₃): δ 1.30 (s, 6H), 2.19 (s, 3H), 2.32 (d, J=4.8 Hz, 2H),2.35 (s, 3H), 5.84 (s, 1H), 6.22 (t, J=4.8 Hz, 1H), 9 6.47 (d, J=15.1Hz, 1H), 6.58 (d, J=11.0 Hz, 1H), 7.05-7.18 (m, 3H), 7.38-7.55 (m, 4H).

Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-cyano-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate(Compound C21)

To a solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)trienoate (Compound C14, 87 mg, 0.18 mmol) in THF (10 mL) were addedtetrakis(triphenylphosphine)palladium (10 mg, 0.01 mmol) and zinccyanide(42 mg, 0.36 mmol). The mixture was heated to 50 °C. for 1 h.Additional quantities of tetrakis(triphenylphosphine)palladium (10 mg,0.01 mmol) and zinc cyanide (42 mg, 0.36 mmol) were added and themixture heated to 50° C. for another 1 h. The reaction was quenched withwater (5 mL), extracted with ethyl acetate (2×20 mL), and the combinedorganic layer was washed with water, followed by brine. The organiclayer was dried (MgSO₄) and solvent removed under reduced pressure.After silicagel chromatography the title compound was isolated as asolid.

¹H NMR (CDCl₃): δ 1.29 (s, 6H), 1.30 (t, J 7.1 Hz, 3H), 2.26 (s, 3H),2.39 (s, 3H), 2.41 (d, J=4.8 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 5.83 (s,1H), 6.41 (d, J=15.0 Hz, 1H), 6.61 (d, J=11.0 Hz, 1H), 6.87 (t, J=4.8Hz, 1H), 7.01 (dd, J=11.0, 15.0 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.44(dd, J=2.0, 8.2 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H).

Ethyl 7-[4,4-dimethyl-3,4-dihydro 1(2H)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound22a) Ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (CompoundC22b)

To a solution of ethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5, 128 mg, 0.4 mmol) in THF (10 mL) and ethanol (10 mL), wasadded O-ethylhydroxylamine hydrochloride (280 mg, 2.8 mmol), sodiumacetate trihydrate (600 mg, 4.4 mmol) and the mixture was stirred atambient temperature for 80 h. The reaction mixture was diluted withethyl acetate (50 mL) and washed with water (10 mL) and brine (50 mL).The organic phase was dried over MgSO₄ and then concentrated in vacuo toa yellow oil. Purification by column chromatography (silica, 10%EtOAc-hexane) followed by HPLC separation (partisil 10, 10%EtOAc-hexane) afforded the title compounds as white solid in the ratiosof 1 (syn): 7 (anti).

Ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (CompoundC22a)

¹H NMR (CDCl₃): δ 1.27-1.39 (m, 12H), 1.88 (t, J=6.3 Hz, 2H), 2.25 (s,3H), 2.39 (s, 3H), 2.56 (t, J=6.5 Hz, 2H), 4.19 (m, 4H), 5.81 (s, 1H),6.34 (d, J=15.0 Hz, 1H), 6.57 (d, J 11.0 Hz, 1H), 7.03 (dd, J=11.4, 15.0Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.46 (dd, J=2.0, 8.6 Hz, 1H), 8.65 (d,J=2.0 Hz, 1H).

Ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-napthth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C22b)

¹H NMR (CDCl₃): δ 1.28-1.31 (m, 9H), 1.36 (t, J=8.2 Hz, 3H), 1.73 (t,J=6.9 Hz, 2H) 2.27 (s, 3H), 2.40 (s, 3H), 2.82 (t, J=6.9 Hz, 2H), 4.20(q, J=7.2 Hz, 2H), 4.3 (q, J=7.1 Hz, 2H), 5.83 (s, 1H), 6.38 (d, J=15.1Hz, 1H), 6.59 (d, J=11.0 Hz, 1H), 7.03 (dd, J=11.2, 15.1 Hz, 1H), 7.32(d, J=8.3 Hz, 1H), 7.42 (dd, J=2.1, 8.2 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H).

7-[4,4-dimethyl-3,4-dihydro-1(2H)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C24)

To a solution of ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (CompoundC22a, 7.8 mg, 0.02 mmol) in THF (1 mL) and ethanol (1 mL), was added 1Mlithium hydroxide (0.08 mL, 0.08 mmol) and the mixture was stirred atambient temparature for 8 days. Thereafter the reaction mixture wasdiluted with Et₂O:EtOAc (1:1, 10 ml) and acidified with 10% HCl to pH 4.The organic layer was washed with water (5 mL), brine (10 ml), dried(MgSO₄) and the solvent was removed under reduced pressure.Recrystallization from EtOAc/hexane gave the title compound as a paleyellow solid.

¹H NMR (CDCl₃): δ 1.32 (s, 6H), 1.36 (t, J=7.1 Hz, 3H), 1.88(t, J=8.7Hz, 2H), 2.25 (s, 3H), 2.39 (s, 3H), 2.55 (t, J=6.5 Hz, 2H), 4.20 (q,J=7.0 Hz, 2H), 5.84 (s, 1H), 6.36 (d, J=15.0 Hz, 1H), 6.58 (d, J=11.0Hz, 1H), 7.03 (dd, J=11.2, 15.1 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.47(dd, J=2.0, 8.6 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H).

7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C25)

To a solution of ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (CompoundC22b, 40 mg, 0.1 mmol) in THF (2 mL) and ethanol (2 mL), was added 1Mlithium hydroxide (2 mL, 2 mmol) and the mixture was stirred at ambienttemparature for 3 days and thereafter at 50°°C. for 8 h. The reactionmixture was diluted with Et₂O:EtOAc (1:1, 10 ml), and then acidifiedwith 10% HCl to pH 4. The organic layer was washed with water (5 mL),brine (10 ml), dried (MgSO₄) and the solvent was removed under reducedpressure. Recrystallization from EtOAc/hexane gave the title compound asa pale yellow solid.

1H NMR (CDCl₃): δ 1.30 (s, 6H), 1.36 (t, J=7.0 Hz, 3H), 1.73 (t, J=7.0Hz, 2H) 2.28 (s, 3H), 2.41 (s, 3H), 2.81 (t, J=6.9 Hz, 2H), 4.25 (q,J=7.1 Hz, 2H), 5.86 (s, 1H), 6.41 (d, J=15.0 Hz, 1H), 6.60 (d, J=11.4Hz, 1H), 7.03 (dd, J=11.4, 15.1 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.42(dd, J=2.1, 8.4 Hz, 1H), 8.09,(d, J=2.0 Hz, 1H).

(−/+)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C26)

To a solution of (−/+)ethyl 7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-hydroxy-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound C13,67 mg, 0.19 mmol) in CH₂Cl₂ (1 mL) were added N,N-diisopropylethylamine(91 mg, 1.1 mmol), chloromethyl methyl ether (294 mg, 2.3 mmol) and themixture was stirred at ambient temparature for 12 h. Then the reactionmixture was diluted with water (5 mL) and Et₂O (25 mL) and washed withwater (10 mL) and brine (10 mL). The organic phase was dried over MgSO₄and concerntrated in vacuo to a yellow oil. Purification by flash columnchromatography (silica, 10% EtOAc-hexane) followed by reverse phase HPLCseparation (partisil 10 ODS-2, 5% H₂O-AcCN) afforded the title compoundas a pale yellow oil.

¹H NMR (CDCl₃): δ 1.24 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.34 (s, 3H),1.55-1.60(m, 1H), 1.91-2.05 (m, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 3,48(s,3H), 4.16 (q, J=7.1 Hz, 2H), 4.65 (t, J=4.7 Hz, 1H), 4.76(d, J=7.0 Hz,1H), 4.87(d, J=7.0 Hz, 1H), 5.80 (s, 1H), 6.33 (d, J=15.2 Hz, 1H), 6.55(d, J=11.5 Hz, 1H), 7.01 (dd, J=11.1, 15.0 Hz, 1H), 7.31 (d, J=8.3 Hz,1H), 7.37 (dd, J=2.1, 8.4 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H).

(+/−)7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-TrienoicAcid (Compound C27)

Employing the same general procedure as for the preparation of7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C25), (−/+)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C26, 20 mg, 0.05 mmol) was converted into the title compound(white solid).

¹H NMR (acetone-d₆): δ 1.23 (s, 3H), 1.30 (s, 3H), 1.55-1.60 (m, 1H),1.89-1.97 (m, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 3,40 (s, 3H), 4.59 (t,J=3.9 Hz, 1H), 4.72 (d, J=6.9 Hz, 1H), 4.81 (d, J=7.0 Hz, 1H), 5.85 (s,1H), 6.49 (d, J=15.1 Hz, 1H), 6.66 (d, J=11.3 Hz, 1H), 7.12 (dd, J=11.1,15.1 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.43 (dd, J=2.1, 8.3 Hz, 1H), 7.49(d, J=2.0 Hz, 1H).

Ethyl7-[4,4-dimethyl-3,4-dihydro-1-(trimethylsiloxy)-naphth-2-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C28)

To a solution of ethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5, 114 mg, 0.33 mmol) in anhydrous THF (10 mL) was addedsodium bis-(trimethylsilyl) amide (0.36 ml, 0.36 mmol) at −78° C. underargon. The reaction was stirred at −78° C. for 20 minutes. To thisreaction solution was then added a solution of trimethylsilylchloride(70.8 mg, 0.65 mmol) in HMPA (0.1 mL) and anhydrous THF (5 ml) at −78°C. The reaction was allowed to stir at −78° C. for 2 h. Then thereaction mixture was diluted with Et₂O (25 mL) and washed with water (10mL), brine (10 mL). The organic phase was dried over MgSO₄ andconcerntrated in vacuo to a yellow oil. The product was purified byflash column chromatography (silica, 10% EtOAc-hexane) to afford thetitle compound as a pale yellow oil.

¹H NMR (acetone-d₆): δ 0.26 (s, 9H), 1.23 (t, J=7.1 Hz, 3H), 1.26 (s,6H), 2.25 (m, 5H), 2.37 (m, 3H), 4.08 (q, J=7.1 Hz, 2H), 5.15 (t, J=4.6Hz, 1H), 5.83 (s, 1H), 6.48 (d, J=15.1 Hz, 1H), 6.65 (d, J 11.0 Hz, 1H),7.13 (dd, J=11.1, 15.0 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.40 (dd, J=2.1,8.1 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H).

(+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl-naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29a) (+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(SR)-tetrahydropyranoxy)-3,7-dimethyl-naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29b)

To a solution of (−/+)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-hydroxy-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C13, 110 mg, 0.3 mmol) in anhydrous CH₂Cl₂ (2 mL) was added3,4-dihydro-2H-pyran (62 mg, 0.7 mmol) followed by pyridiniump-toluenesulfonate (10 mg, 0.04 mmol). The reaction mixture was stirredat ambient temperature for 24 h. The reaction mixture was diluted withEt₂O (20 mL) and washed successively with saturated NaHCO₃ (10 mL),water (10 mL) and brine (10 mL). The organic phase was dried over MgSO₄and concerntrated in vacuo to a yellow oil. Purification by flash columnchromatography (silica, 15% EtOAc-hexane) followed by reverse phase HPLCseparation (partisil 10 ODS-2, 5% H₂O-AcCN) afforded the title compoundsas pale yellow oils.

(+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl-naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29a)

¹H NMR (CDCl₃): δ 1.25-1.31 (m, 9H), 1.52-2.03 (m, 10H), 2.24 (s, 3H),2.38 (s, 3H), 3.50-3.60 (m, 1H), 4.01-4.07 (m, 1H), 4.12 (q, J=7.1 Hz,2H), 4.77 (t, J=4.5 Hz, 1H), 4.94 (t, J=3.5 Hz, 1H), 5.80 (s, 1H), 6.32(d, J=15.0 Hz, 1H), 6.56 (d, J=11.5 Hz, 1H), 7.02 (dd, J=11.1, 15.0 Hz,1H), 7.28 (d, J=8.3 Hz, 1H), 7.36 (dd, J=2.1, 8.3 Hz, 1H), 7.62 (d,J=2.0 Hz, 1H).

(+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(SR)-tetrahydropyranoxy)-3,7-dimethyl--naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29b)

¹H NMR (CDCl₃): δ 1.25-1.32 (m, 9H), 1.52-2.08 (m, 10H), 2.45 (s, 3H),2.38 (s, 3H), 3.54-3.61 (m, 1H), 3.97-4.03 (m, 1H), 4.14 (q, J=7.1 Hz,2H), 4.68 (t, J=5.0 Hz, 1H), 4.87 (t, J=4,4 Hz, 1H), 5.81 (s, 1H), 6.34(d, J=15.2 Hz, 1H), 6.54 (d, J=11.0 Hz, 1H), 7.01 (dd, J=11.2, 15.1 Hz,1H), 7.30-7.40 (m, 3H)

(+/−)7-[4,4-Dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl--naphth-2-yl]hepta-2(E),4(E),6(E)-trienoicacid (Compound C31)

Employing the same general procedure as for the preparation of7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C25), (+/−)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl-naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29a, 15 mg, 0.03 mmol) was converted into the title compound(white solid).

¹H NMR (acetone-d₆): δ 1.24 (s, 3H) 1.29 (s, 3H), 1.52-2.03 (m, 10H),2.26 (s, 3H), 2.37 (s, 3H), 3.56-3.61 (m, 1H), 3.99-4.03 (m, 1H), 4.70(t, J=4.5 Hz, 1H), 4.91 (t, J=3,7 Hz, 1H), 5.80 (s, 1H), 6.49 (d, J=15.0Hz, 1H), 6.66 (d, J=11.3 Hz, 1H), 7.13 (dd, J=11.1, 15.0 Hz, 1H), 7.34(d, J=8.3 Hz, 1H), 7.42 (dd, J=2.1, 8.3 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H).

7-Acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33)

To a solution of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37, 698 mg, 2.5 mmol) in anhydrous THF (15 mL) was added(1-ethoxyvinyl)tributyltin (1.8 g, 5 mmol) andbis(triphenylphosphine)palladium(II) chloride (20 mg). The resultantmixture was refluxed under argon atmosphere for 24 h. The reactionmixture was cooled to ambient temperature and quenched with 10% HCl(5mL), stirred for 20 mimutes and extracted with Et₂O (3×20 mL). Theorganic layer was washed with water (10 mL), saturated NaHCO₃ (10 mL),brine (10 mL) and dried over MgSO₄. The crude material was purified byflash colunm chromatography (silica, 5% EtOAc-hexane) to afford thetitle compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.60 (t, J=6.9 Hz, 2H), 1.84 (s, 3H),1.97 (s, 3H), 2.49 (t, J=6.9 Hz, 2H), 2.57 (s, 3H), 7.35 (d, J=8.3 Hz,1H), 7.73 (dd, J=2.0, 8.2 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H).

3-[1(2H)-(Propyliden-2-yl))-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-nitrile(Compound C34)

To a slurry o NaH (117 mg, 4.8 mmol ) in anhydrous THF (10 mL) was addeda solution of ethylcyanomethylphosphonate (947 mg, 5.4 mmol) in THF (2mL) at −78° C. under argon atmosphere. The reaction was allowed to warmto ambient temperature and a solution of7-acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33, 394 mg, 1.6 mmol) in 5 mL of THF was added dropwise. Theresultant reaction was stirred for 16 h at ambient temperature andquenched with water (5 mL). After extraction with EtOAc (2×10 mL), thecombined organic layer was dried over MgSO₄, and concentrated in vacuo.The crude product was purified by flash colunm chromatography (silica,5% EtOAc-hexane) to afford the title compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.60 (t, J=7.0 Hz, 2H), 1.85 (s, 3H),1.96 (s, 3H), 2.45 (s, 3H), 2.49 (t, J=6.8 Hz, 2H), 5,59 (s, 1H),7.24-7.35 (m, 3H).

3-[1(2H)-(Propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-aldehyde(Compound C35)

To a solution of3-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-onitrile(Compound C34, 311 mg, 1.2 mmol) in anhydrous CH₂Cl₂ (10 ml) was added asolution of diisobutylaluminum hydride (1M in CH₂Cl₂) (2.8 ml, 2.8 mmol)dropwise at −78° C., under argon atmosphere. The reaction was allowed tostir at −78° C. for 6 h. A mixture of H₂O (10 ml) and CH₂Cl₂ (10 ml) wasadded and the resultant gel was filtered. The filtrate was concentratedin vacuo to a yellow oil. Purification by flash column chromatography(silca, 10% EtOAc-hexane) afforded the title compound as a pale yellowoil.

¹H NMR (CDCl₃): δ 1.26 (s, 6H), 1.62 (t, J=7.0 Hz, 2H), 1.86 (s, 3H),1.98 (s, 3H), 2.50 (t, J 6.9 Hz, 2H), 2.57 (s, 3H), 6.40 (d, J=9.3 Hz,1H), 7.35-7.39 (m, 2H), 7.45 (d, J=1.9 Hz, 1H), 10.17 (d, J=7.9 Hz, 1H).

Ethyl-7-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethyl-naphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)-trienoate(Compound C36)

Employing the same general procedure as for the preparation of ethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5),3-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-aldehyde(Compound C35, 178 mg, 0.6 mmol) was converted into the title compound(pale yellow thick syrup).

¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.27 (t, J=7.0 Hz, 3H), 1.60 (t, J=6.9Hz, 2H), 1.84 (s, 3H), 1.98 (s, 3H), 2.24 (s,3H), 2.37 (s, 3H), 2.48 (t,J=6.7 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H), 5.79 (s, 1H), 6.33 (d, J=14.9 Hz,1H), 6.54 (d, J=10.9 Hz, 1H), 6.98 (dd, J=11.0, 15.0 Hz, 1H), 7.25-7.28(m, 2H), 7.36 (s, 1H).

7-Bromo-1(2H)-(phenylbenzyliden-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C37)

Employing the same general procedure as for the preparation of 7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene (CompoundA37), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G,1.0 g, 3.96 mmol) was converted into the title compound (white solid)using titanium trichloride (5 g, 32 mmol), lithium wire (0.7 g, 100mmol) and benzophenone (800 mg, 4.4 mmol).

¹H NMR (CDCl₃): δ 1.31 (s, 6H), 1.66 (t, J=6.6 Hz, 2H), 2.52 (t, J=6.8Hz, 2H), 6.92 (d, J=1.7 Hz, 1H), 6.98-7.00 (m, 2H), 7.15-7.21 (m, 6H),7.25-7.36 (m, 4H).

7-Acetyl-1(2H)-(phenylbenzyliden-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C38)

Employing the same general procedure as for the preparation of7-acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33),7-bromo-1(2H)-(phenylbenzyliden-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C37, 255 mg, 0.63 mmol) was converted into the title compound(colorless oil) using (1-ethoxyvinyl)tributyltin (353 mg, 0.97 mmol) andbis(triphenylphosphine)palladium(II) chloride (20 mg).

¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.70 (t, J=6.4 Hz, 2H), 1.99 (s, 3H),2.57 (t, J=6.7 Hz, 2H), 7.01-7.04 (m, 2H), 7.12-7.45 (m, 10H), 7.65 (dd,J=1.9, 8.3 Hz, 1H).

3-(1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2(E)-enonitrile(Compound C39)

Employing the same general procedure as for the preparation of3-(1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthyl)but-2(E)-enonitrile(Compound C34), the7-acetyl-1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound 38, 206 mg, 0.56 mmol) was converted into the title compound(colorless oil) using 327 mg (1.85 mmol) of ethylcyanomethylphosphonateand 40.3 mg (1.68 mmol) of sodium hydride.

¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.70 (t, J=6.3 Hz, 2H), 2.03 (s, 3H),2.57 (t, J=6.8 Hz, 2H), 4.88 (s, 1H), 7.01 (dd, J=2.0, 7.3 Hz, 2H),7.14-7.37 (m, 11H).

3-(1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2(E)-enaldehyde(Compound C40)

Employing the same general procedure as for the preparation of3-(1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthyl)-but-2(E)-enaldehyde(Compound C35),3-(1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2-enonitrile(Compound C39, 156 mg, 0.40 mmol) was converted into the title compound(pale yellow solid) using 0.9 ml (0.88 mmol) of diisobutylaluminumhydride (1M in CH₂Cl₂).

¹H NMR (CDCl₃): δ 1.35 (s, 6H), 1.70 (t, J=6.5 Hz, 2H), 2.04 (s, 3H),2.57 (t, J=6.7 Hz, 2H), 5.88 (d, J=7.7 Hz, 1H), 7.02 (dd, J=1.5, 7.4 Hz,2H), 7.12-7.36 (m, 11H), 9.98 (d, J=7.8 Hz, 1H).

Ethyl7-[4,4-dimethyl-3,4-dihydro-1(2H)-(phenylbenzylidenyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C41)

Employing the same general procedure as for the preparation of ethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5),3-(1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2(E)-enaldehyde(Compound C40, 101 mg, 0.26 mmol) was converted into the title compound(pale yellow thick oil).

¹H NMR (CDCl₃): δ 1.28 (t, J=7.1 Hz, 3H), 1.34 (s, 6H), 1.69 (t, J=6.3Hz, 2H), 1.85 (s, 3H), 2.32 (s, 311), 2.54 (t, J=6.9 Hz, 2H), 4.14 (q,J=7.1 Hz, 2H), 5.74 (d, J=8.7 Hz, 1H), 5.77 (s, 1H), 6.15 (d, J=14.9 Hz,1H), 6.80 (dd, J=11.2, 15.0 Hz, 1H), 7.04-11 7.36 (m, 13H).

7-Bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C42)

In a flame dried round bottom flask7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 2.0 g,7.93 mmol) was dissolved in anhydrous THF (50 ml) and3,4,5,6,-tetrahydro-2(H)-pyrimidinone (DMPU) (11.5 ml, 95.16 mmol) wasadded, under argon atmosphere. The reaction was then cooled to −20° C.and a solution of t-butyl magnesium chloride (16 ml, 31.7 mmol) (2 M inEt₂O) was added dropwise and stirred at −20° C. for 2 h and at ambienttemperature for 1 h, under argon atmosphere. The reaction was quenchedat 0° C. with saturated ammonium chloride solution (20 ml) and extractedwith EtOAc (2×50 ml). The combined extract was washed with water (20ml), brine (20 ml) and dried over MgSO₄. The solvent was evaporatedunder reduced pressure to afford a yellow oil. To this yellow oil wereadded MeOH (50 ml) and p-tolylsulfonic acid (100 mg). The resultantreaction solution was heated in an oil bath (60° C.) for 3 h. Thereaction was cooled and quenched with water (20 ml), extracted withEtOAc (2×50 ml). The combined extract was washed with saturated NaHCO₃(20 ml), water (20 ml), brine (20 ml), and dried over MgSO₄. The solventwas concentrated in vacuo and the title compound was obtained as acolorless oil after purification by flash chromatography (silica,hexane).

¹H NMR (CDCl₃): δ 1.17 (s, 6H), 1.32 (s, 9H), 2.10 (d, J=5.0 Hz, 2H),5.95 (t, J=4.9 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.24 (dd, J=2.1, 8.3 Hz,1H), 7.74 (d, J=2.0 Hz, 1H).

7-Acetyl-1-(1,1-dimethylethyl)-3,4,-dihydro-4,4-dimethylnaphthalene(Compound C43)

Employing the same general procedure as for the preparation of7-acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33),7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C42, 539 mg, 1.84 mmol) was converted into the title compound(white solid), using (1-ethoxy vinyl)tributyltin (2.6 g, 7.36 mmol) andbis(triphenylphosphine)palladium(II) chloride (80 mg).

¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.39 (s, 9H), 2.16 (d, J=4.9 Hz, 2H),2.60 (s ,3H), 6.00 (t, J=4.9 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.75 (dd,J=1.7, 8.0 Hz, 1H), 8.29 (d, J=1.8 Hz, 1H).

3-[1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethyl-naphthyl]-2-but-2(E)-enonitrile(Compound C44)

Employing the same general procedure as for the preparation of3-(1-propylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthyl)but-2(E)-enonitrile(Compound C34),7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C43, 326 mg, 1.26 mmol) was converted into the title compound(white solid) using 742 mg (4.19 mmol) of ethylcyanomethylphosphonateand 91 mg (3.80 mmol) of sodium hydride.

¹H NMR (CDCl₃): δ 1.22 (s, 6H), 1.36 (s, 9H), 2.14 (d, J=4.9 Hz, 2H),2.47 (s ,3H), 5.58 (s, 1H), 6.00 (t, J=4.9 Hz, 1H), 7.26 (dd, J=2.0, 8.2Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H).

3-[1,1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethyl-naphth-7-yl]-but-2(E)-enaldehyde(Compound C45)

Employing the same general procedure as for the preparation of3-(1-propylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthyl)-but-2(E)-enaldehyde(Compound C35),(E)-3-(1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthyl)-but-2)E)-enonitrile(Compound C45, 256 mg, 0.95 mmol) was converted into the title compound(pale yellow solid) using 2.8 ml (2.84 mmol) of diisobutylaluminumhydride (1M in CH₂Cl₂).

¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.30 (s, 9H), 2.16 (d, J=5.0 Hz, 2H),2.60 (s, 3H), 6.01 (t, J=4.9 Hz, 1H), 6.41 (d, J=7.8 Hz, 1H), 7.38 (m,2H), 7.86 (s, 1H), 10.19 (d, J=8.0 Hz, 1H).

Ethyl7-[4,4-dimethyl-3,4-dihydro-1-(1.1-dimethylethyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C46)

Employing the same general procedure as for the preparation of ethyl3,7-dimethyl-7-[5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C5,(E)-3-[1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethyl-naphthyl]-2-butene-1-aldehyde(Compound C45, 82.6 mg, 0.29 mmol) was converted into the title compound(pale yellow solid).

¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.28 (t, J=7.1 Hz, 3H), 1.39 (s, 9H),2.15 (d, J=4.9 Hz, 2H), 2.28 (s, 311), 2.40 (s, 31), 4.15 (q, J=7.1 Hz,2H), 5.83 (s, 1H), 5.97 (t, J=4.9 Hz, 1H), 6.36 (d, J=15.2 Hz, 1H), 6.54(d, J=11.5 Hz, 1H), 7.00 (dd, J=11.1, 15.0 Hz, 1H), 7.31 (s, 2H), 7.78(s, 1H).

(+/−) Ethyl4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate(Compound D1)

To a refluxing solution of zinc dust (0.15 g, 20 mesh, activated priorto use by washing with 2% of hydrochloric acid, water, 95% ethanol,acetone and anhydrous ether, then dried in vacuum for several hours) in6 ml of dry benzene was slowly added a mixture of bromo ethyl acetate(0.082 ml, 0.74 mmol) and ethyl4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate(Compound D10, 0.13 g, 0.371 mmol) in 6 ml of dry benzene. The resultingmixture was refluxed for 2 h then cooled to room temperature. Theprecipitate was filtered through celite and the filtrate was washed withcold 15% sulfuric acid. The organic phase was washed with saturatedsodium bicarbonate, brine, dried over Na₂SO₄, filtered and concentratedto give a red oil. Purification by flash chromatography (silica gel, 30%ethyl acetate in hexane) afforded the title compound as a red oil.

¹H NMR (CDCl₃): δ 1.28 (t, J=7.14 Hz, 3H), 1.34 (3H, s), 1.37 (s, 3H),1.43 (t, J=7.14 Hz, 3H), 1.81 (m, 2H), 2.12 (m, 2H), 2.90 (q, J=7.14 Hz,2H), 4.22 (q, J=7.14 Hz, 2H), 4.42 (q, J=7.14 Hz, 2H), 7.46 (d, J=8.43Hz, 1H), 7.80 (dd, J=2.07, 6.35 Hz, 1H), 7.91 (d, J=8.55 Hz, 2H), 8.17(d, J=8.55 Hz, 2H), 8.20 (d, J=2.20 Hz, 1H).

Ethyl4-[(5,5-dimethyl-8(7H)-(carbethoxymethylideneyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2a) Ethyl4-[(5,5-dimethyl-8-(carbethoxymethyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2b)

A solution of (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate(Compound D1, 108 mg, 0.25 mmol), DCC (55.9 mg, 0.271 mmol) and CuCl(36.6 mg, 0.37 mmol) in 8 ml of dry benzene was heated under reflux for7 days. After cooling to room temperature, the solids were filtered outand the solution was extracted with ethyl acetate. The combined organiclayer was washed with brine and dried over Na₂SO₄. The solvent wasremoved under reduced pressure, the crude material was purified by flashchromatography (silicagel, 10% ethyl acetate in hexane) to afford thepure title compounds as red oils.

Ethyl4-[(5,5-dimethyl-8(7H)-(carbethoxymethylidenyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2a)

¹H NMR (CDCl₃): δ 1.35 (m, 9H), 1.44 (t, J=7.14 Hz, 3H), 1.79 (t, J=6.75Hz, 2H), 3.29 (t, J=6.59 Hz, 2H), 4.27 (q, J=7.14 Hz, 2H), 4.44 (q,J=7.14 Hz, 2H), 6.47 (s, 1H), 7.55 (d, J=8.42 Hz, 1H), 7.97 (m, 3H),8.22 (m, 3H).

Ethyl4-[(5,5-dimethyl-8-(carbethoxymethyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2b)

¹H NMR (CDCl₃): δ 1.22 (t, J=7.10 Hz, 3H), 1.35 (s, 6H), 1.44 (t, J=7.14Hz, 3H), 2.32 (d, J=4.39 Hz, 2H), 3.56 (s 2H), 4.17 (q, J=7.14 Hz, 2H),4.44 (q, J=7.14 Hz, 2H), 6.20 (t, J=4.45 Hz, 1H), 7.48 (d, J=8.80 Hz,1H), 7.81 (m, 2H), 7.92 (d, J=8.49 Hz, 2H), 8.20 (d, J=8.48 Hz, 2H).

Ethyl 4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoate (CompoundD3)

A solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate(Compound D10, 0.13 g, 0.371 mmol) (40 mg, 0.114 mmol), NaOAc (29.3 mg,0.286 mmol) and methoxy amine hydrochloride (14.3 mg, 0.137 mmol) in 3ml of EtOH and 2 ml of THF was stirred at room temperature for twoweeks. The solvent was distilled off and the residue was diluted withethyl acetate. The solution was washed with NaHCO₃ (sat.), water, brineand dried over Na₂SO₄. The solvent was removed under reduced pressure,the residue was purified by flash chromatography to afford the titlecompound as a red solid (34.8 mg).

¹H NMR (CDCl₃): δ 1.35 (s, 3H), 1.44 (t, J=7.14 Hz, 3H), 1.78 (t, J=6.96Hz, 2H), 2.83 (t, J=6.90 Hz, 2H), 4.06 (s, 3H), 4.43 (q, J=7.14 Hz, 2H),7.51 (d, J=8.48 Hz, 1H), 7.82 (dd, J=2.20, 6.35 Hz, 1H), 7.96 (d, J=8.55Hz, 2H), 8.21 (d, J=8.48 Hz, 2H), 8.56 (d, J=2.14 Hz, 1H).

4-[(8(7H)-Anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoic acid(Compound D4)

A solution of ethyl 4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoate (CompoundD3, 57.7 mg, 0.16 mmol) and 2 ml of aqueous NaOH (12%) in 4 ml of THFand 2 ml of EtOH was stirred overnight at room temperature. The reactionwas acidified with 10% HCl (to pH 4 and extracted with EtOAc. Thecombined organic layer was washed with water and brine, and dried overNa₂SO₄. Solvent was removed under reduced pressure of afford the titlecompound as a red solid.

¹H NMR (acetone-d₆): δ 1.35 (s, 3H), 1.78 (t, J=6.96 Hz, 2H), 2.82 (t,J=6.90 Hz, 2H), 4.00 (s, 3H), 7.67 (d, J=8.54 Hz, 1H), 7.90 (dd, J=2.20,6.59 Hz, 1H), 8.03 (d, J=8.66 Hz, 2H), 8.24 (d, J=8.48 Hz, 2H), 8.54 (d,J=2.14 Hz, 1H).

(+/−) Ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D5)

To a solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate(Compound D10, 60 mg, 0.171 mmol) in 2 ml of TBF and 7 ml of EtOH at 0°C. was added NaBH₄ (6.5 mg, 0.171 mmol) and the mixture stirred for 3 h.The reaction was quenched by slow addition of cold water. Solvent wasremoved under reduced pressure and the residue was extracted with ethylacetate. The organic layer was washed with brine, dried (MgSO₄) andsolvent removed under reduced pressure. The crude product was purifiedby flash chromatography (silica, ethyl acetate/hexane, 1:3) to affordthe title compound as a red oil.

¹H NMR (CDCl₃): δ 1.31 (s, 3H), 1.38 (s, 3H), 1.43 (t, J=7.14 Hz, 3H),1.68 (m, 1H), 1.92 (m, 2H), 2.13 (m, 1H), 4.42 (q, J=7.14 Hz, 2H), 4.85(m, 1H), 7.49 (d, J=8.48 Hz, 1H), 7.85 (dd, J=2.2, 6.29 Hz, 1H), 7.94(d, J=8.61 Hz, 2H), 8.05 (d, J=2.13 Hz, 1H), 8.20 (d, J=8.55 Hz, 2H).

(+/−) Ethyl4-[(5,5-dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D6)

To a solution of (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH₂Cl₂ at 0° C. wasadded isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed bychloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixturewas stirred at room temperature for 12 h. Solvent was removed underreduced pressure, the residue was dissolved in ethyl acetate and thesolution was washed with NaHCO₃ (sat.), and brine. The organic layer wasdried (MgSO₄). The solvent was removed under reduced pressure, theresidue was purfied by flash chromatography (silica, ethylacetate:hexane, 1:3) to afford the title compound as a red oil.

¹H NMR (CDCl₃): δ 131 (s, 3H), 1.39 (s, 3H), 1.43 (t, J=7.08 Hz, 3H),1.64 (m, 1H), 2.07 (m, 3H), 3.52 (s, 3H), 4.43 (q, J=7.08 Hz, 2H), 4.75(t, J=5.06 Hz, 1H), 4.84 (d, J=6.90 Hz, 1H), 4.93 (d, J=6.90 Hz, 1H),7.50 (d, J=8.43 Hz, 1H), 7.83 (dd, J=2.19, 6.29 Hz, 1H), 7.95 (m, 3H),8.19 (d, J=8.55 Hz, 2H).

(+/−)4-[(5,5-Dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoicacid (Compound D7)

Using the same procedure as for the preparation of4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoic acid(Compound D4), (+/−) ethyl4-[(5,5-dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D6, 34 mg, 0.093 mmol) was converted into the title compound(red solid).

¹H NMR (acetone-d₆): δ 132 (s, 3H), 1.37 (s, 3H), 1.63 (m, 1H), 1.99 (m,3H), 3.45 (s, 3H), 4.75 (t, J=6.1 Hz, 1H), 4.80 (d, J=6.96 Hz, 1H), 4.89(d, J=6.96 Hz, 11), 7.62 (d, J=8.55 Hz, 1H), 7.84 (dd, J=2.19, 6.29 Hz,1H), 8.00 (m, 3H), 8.22 (d, J=8.55 Hz, 2H).

3,4-dihydro-4,4-dimethyl-7-nitro-naphthalen-1(2H)-one (Compound D8)

To 1.7 mL (3.0 g, 30.6 mmol, 18M) H₂SO₄ at −5_(i)C. (ice-NaCl bath) wasslowly added 783.0 mg (4.49 mmol) of3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. A solution of HNO₃ (426.7mg 6.88 mmol, 0.43 mL, 16M), and 1.31 g (0.013 mol, 0.74 mL, 18 M) ofH₂SO₄ were slowly added. After 20 min, ice was added and the resultingmixture was extracted with EtOAc. The combined extracts wereconcentrated under reduced pressure to give a yellow oil from which thetitle compound, a pale yellow solid, was isolated by columnchromatography (10% EtOAC/hexanes).

¹H NMR (CDCl₃): δ 8.83 (1H, d, J=2.6 Hz), 8.31 (1H, dd, J=2.8, 8.9 Hz),7.62 (1H, d, J=8.7 Hz), 2.81 (2H, t, J=6.5 Hz), 2.08 (2H, t, J=6.5 Hz),1.45 (6H, s).

3,4-dihydro-4,4-dimethyl-7-amino-naphthalen-1(2H)-one (Compound D9)

A solution of 230.0 mg (1.05 mmol)3,4-dihydro-4,4-dimethyl-7-nitro-naphthalen-1(2H)-one (Compound D8) in5.0 mL of EtOAc was stirred at room temperature with a catalytic amountof 10% Pd-C under 1 atm of H₂ for 24 h. The catalyst was removed byfiltration through a pad of Celite, and the filtrate concentrated underreduced pressure to give the title compound as a dark green oil.

¹H NMR (CDCl₃):_(—)7.30 (1H, d, J=2.7 Hz), 7.22 (1H, d, J=8.4 Hz), 6.88(1H, dd, J=2.7, 8.5 Hz), 2.70 (2H, t, J=6.6 Hz), 1.97 (2H, t, J=6.6 HZ),1.34 (6H, s).

Ethyl 4-[(5,6-dihydro-5,5-dimethyl-8(7)-one-naphthalen-2-yl)azo]-benzoate (Compound D10)

To a solution of 198.7 mg (1.05 mmol)3,4-dihydro-4,4-dimethyl-7-amino-naphthalen-1(2H)-one (Compound D9) in5.0 mL glacial acetic acid was added 180.0 mg (1.00 mmol) of ethyl4-nitrosobenzoate. The resulting solution was stirred overnight at roomtemperature, and then concentrated under reduced pressure. The productwas isolated from the residual oil as a red solid, by columnchromatography (15% EtOAc-hexanes).

¹H NMR (CDCl₃): δ 8.57 (1H, d, J=2.0 Hz), 8.19 (2H, d, J=8.4 Hz), 8.07(1H, d, J=8.0 Hz), 7.94 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=8.6 Hz), 4.41(2H, q, J=7.1 Hz), 2.79 (2H, t, J=6.6 Hz), 2.07 (2H, t, J=7.02 Hz), 1.44(6H, s), 1.42 (3H, t, J=7.1 Hz).

Ethyl4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfony)oxy-naphthalen-2-yl)azo]-benzoate(Compound D11)

To a solution of 90.4 mg sodium bis(trimethylsilyl)amide (0.48 mmol,0.48 mL of a 1.0 M THF solution) in 2.0 mL THF at −78° C., was added153.0 mg (0.437 mmol) of ethyl4-[(5,6-dihydro-5,5-dimethyl-8(7H)-one-naphthalen-2-yl) azo]-benzoate(Compound D10) in 2.0 mL THF. The dark red solution was stirred at−78_(i)C for 30 min and then 204.0 mg (0.520 mmol)2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine was added asa solution in 2.0 mL THF. The reaction mixture was allowed to warm toroom temperature and after 3 h was quenched by the addition of H₂O. Theorganic layer was concentrated to a red oil under reduced pressure. Theproduct was isolated by column chromatography (25% EtOAc/hexanes) as ared oil.

¹H NMR (CDCl₃): d 8.21 (2H, d, J=8.6 Hz), 7.96 (2H, d, J=8.6 Hz), 7.94(2H, m), 7.49 (1H, d, J=8.2 Hz), 6.08 (1H, t, J=2.5 Hz), 4.42 (2H, q,J=7.1 Hz), 2.49 (2H, d, J=4.8 Hz), 1.44 (3H, t, J=7.1 Hz), 1.38 (6H, s).

Ethyl4-[(5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D12)

To a cold solution (−78° C.) of thiophene (0.07 ml, 0.75 mmol) in 1.5 mlof THF was added t-BuLi (0.457 ml, 0.75 mmol, 1.7 M in pentane) andstirred for 2 h. To this solution, ZnCl₂ (168 mg, 1.2 mmol) in 1.5 ml ofTHF was added. The resulting solution was warmed to room temperature,stirred for 1 h and was added (via cannula) to a solution of ethyl4-[(5,6-dihydro-5,5-dimethyl-8-trifluoromethylsulfonyloxy-naphthalen-2-yl)azo]benzoate(Compound D11, 150 mg, 0.30 mmol) andtetrakis(triphenylphosphine)palladium(0) (10.6 mg) in 2.5 ml of THF. Theresulting mixture was heated at 50° C. for 2.5 h. The reaction wasdiluted with sat, aqueous NH₄Cl and extracted with ethyl acetate. Thecombined organic layer was dried over Na₂SO₄ and concentrated to an oil.The crude product was purified by flash chromatography (silica, ethylacetate:hexane 5:95) to afford the title compound as a red foam.

¹H NMR (CDCl₃): δ 1.40 (s, 6H), 1.44 (t, J=7.14 Hz, 3H), 2.41 (d, J=4.82Hz, 2H), 4.42 (q, J=7.14 Hz, 2H), 6.29 (t, J=4.83 Hz, 1H), 7.14 (m, 2H),7.32 (dd, J=1.52, 3.36, 1H), 7.53 (d, J=8.31 Hz, 1H), 7.84 (dd, J=2.08,6.17 Hz, 1H), 7.92 (d, J=8.60 Hz, 2H), 8.03 (d, J=2.07 Hz, 1H), 8.18 (d,J=8.61 Hz, 2H).

4-[(5,5-Dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoicacid (Compound D13)

Using the same procedure as for the preparation of4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoic acid(Compound D4), ethyl4-[(5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound 12, 100 mg, 0.258 mmol) was converted into the title compound(red solid).

¹H NMR (acetone-d₆): δ 1.40 (s, 6H), 2.43 (d, J=4.83 Hz, 2H), 2.82 (b,1H), 6.32 (t, J=4.88 Hz, 1H), 7.19 (m, 2H), 7.50 (d, J=4.88 Hz, 1H),7.65 (d, J=8.24 Hz, 1H), 7.95 (m, 4H), 8.21 (d, J=8.55 Hz, 2H).

3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (Compound D14a):and 3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (CompoundD14b)

To a cold (0° C.) mixture of aluminum chloride (26.3 g, 199.0 mmols) indichloromethane (55 mL) were added acetylchloride (15 g, 192 mmols) and1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (24.4 g, 152 mmols) indichloromethane (20 mL) over 20 minutes. The reaction mixture was warmedto ambient temperature and stirred for 4 h. Ice (200 g) was added to thereaction flask and the mixture diluted with ether (400 mL). The layerswere separated and the organic phase was washed with 10% HCl (50 mL),water (50 mL), 10% aqueous sodium bicarbonate, and saturated aqueousNaCl (50 mL) and thereafter dried over MgSO₄. The solvent was removed bydistillation to afford a yellow oil which was dissolved in benzene (50mL).

To a cold (0° C.) solution of acetic acid (240 mL) and acetic anhydride(120 mL) was added chromiumtrioxide (50 g, 503 mmols) in small portionsover 20 mins under argon. The mixture was stirred for 30 mins at 0° C.and diluted with benzene (120 mL). The benzene solution prepared above,was added with stirring via an addition funnel over 20 mins. After 8 h,the reaction was quenched by the careful addition of isopropanol (50 mL)at 0° C., followed by water (100 mL). After 15 mins, the reactionmixture was diluted with ether (1100 mL) and water (200 mL), and thenneutralized with solid sodium bicarbonate (200 g). The ether layer waswashed with water (100 mL), and saturated aqueous NaCl (2×100 mL), anddried over MgSO₄. Removal of the solvent under reduced pressure affordeda mixture of the isomeric diketones which were separated bychromatography (5% EtOAc/hexanes).

(Compound D14a): ¹H NMR (CDCl₃): d 8.55 (1H, d, J=2.0 Hz), 8.13 (1H, dd,J=2.0, 8.3 Hz), 7.53 (1H, d, J=8.3 Hz), 2.77 (2H, t, J=6.6 Hz), 2.62(3H, s), 2.05 (2H, t, J=6.6 Hz), 1.41 (6H, s).

(Compound D14b): ¹H NMR (CDCl₃): d 8.10 (1H, d, J=8.1 Hz), 8.02 (1H, d,J=1.6 Hz), 7.82 (1H, dd, J=1.6, 8.1 Hz), 2.77 (2H, t, J=7.1 Hz), 2.64(3H, s), 2.05 (2H, t, J=7.1 Hz), 1.44 (6H, s).

6-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15)

A solution of 1.80 g (8.34 mmol) of a 1:5 mixture of3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (Compound D14a);and 3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (CompoundD14b) in 50 mL benzene was combined with 517.7 mg (8.34 mmol) ofethylene glycol and 20.0 mg (0.11 mmol) of p-toluenesulfonic acidmonohydrate. The resulting solution was heated to reflux for 18 h,cooled to room temperature, and concentrated under reduced pressure. Thetitle compound was isolated by column chromatography (10% EtOAc-hexanes)as a colorless oil.

¹H NMR (CDCl₃): δ 8.01 (1H, d, J=8.2 Hz), 7.51 (1H, s), 7.43 (1H, dd,J=1.7, 6.4 Hz), 4.07 (2H, m), 3.79 (2H, m), 2.74 (2H, t, J=6.5 Hz), 2.04(2H, t, J=7.1 Hz), 1.67 (3H, s), 1.46 (6H, s).

(+/−)6-(2-Methyl-1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxmethyl)-naphthlene(Compound D16)

Using the same procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(carboethoxymethyl)naphthalen-2-yl)azo]benzoate,6-(2-methyl-1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D1),6-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15, 300 mg, 1.15 mmol) was converted to the title product(321 mg, light yellow oil), using zinc dust (0.5 g, pretreated) andbromo ethyl acetate (0.256 ml, 0.30 mmol) in 10 ml of benzene.

¹H NMR (CDCl₃): δ 1.29 (t, J=7.08 Hz, 3H), 1.30 (s, 3H), 1.32 (s, 3H),1.65 (s, 3H), 2.06 (s, 2H), 2.80 (q, J=1.45 Hz, 2H), 3.77 (m, 2H), 4.05(m, 2H), 4.13 (q, J=7.14 Hz, 2H), 4.22 (q, J=7.14 Hz, 2H), 7.30 (dd,J=1.71, 6.54 Hz, 1H), 7.42 (d, J=1.77 Hz, 1H), 7.53 (d, J=8.18 Hz, 1H).

3,4-Dihydro-4,4-dimethyl-1-(carboethoxmethyl)-6-acetyl-naphthalene(Compound D17)

A solution of (+/−)6-(2-methyl-1,3-dioxolan-2-yl)-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene((Compound D16, 321 mg, 0.90 mmol) and catalytic amount of TsOH in 20 mlof benzene was refluxed for 12 h. During the reaction the watergenerated from the reaction was periodically removed by a Dean-Starktrap. The solvent was removed and the residue was purified by columnchromatography (silica, ethyl acetate/hexane (1/3)) to give the titlecompound as an oil (215 mg).

¹H NMR (CDCl₃): δ 1.20 (t, J=7.14 Hz, 3H), 1.33 (s, 6H), 2.30 (d, J=3.42Hz, 2H), 2.60 (s, 3H), 3.50 (s, 2H), 4.16 (q, J=7.14 Hz, 2H), 6.06 (t,J=4.64 Hz, 1H), 7.28 (d, J=2.80 Hz, 1H), 7.76 (, J=1.34, 6.10 Hz, 1H),7.93 (s, 1H).

(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]BenzoicAcid (Compound D18)

To a solution of3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-6-acetyl-naphthalene((Compound D17, 25 mg, 0.10 mmol) and 4-carboxybenzaldehyde (17 mg, 0.13mmol) in 2 ml of MeOH was added aqueous NaOH (0.75 ml, 12%). Thereaction mixture was stirred at room temperature for overnight andquenched by addition of 10% HCl to pH=4.0. The solvent was removed andextracted ethyl acetate, the combined organic layer was washed withwater. The organic layer was dried and concentrated to a white solid.This white solid was dissolved in 1 ml of DMF. To this solution wasadded DMAP (15.2 mg, 0.12 mmol), EDC (22 mg, 0.11 mmol) and 0.5 ml EtOH.The reaction mixture was stirred at room temperature for 5 h andconcentrated in vacuo. The residue was passed through a chromatographiccolumn with ethyl acetate/hexane (1/9) to give the title compound as alight tan solid.

¹H NMR (CDCl₃): δ 1.21 (t, J=7.14 Hz, 3H), 1.36 (s, 6H), 1.42 (t, J=7.14Hz, 3H), 2.33 (d, J=4.46 Hz, 2H), 4.13 (q, J=7.14 Hz, 2H), 4.41 (q,J=7.14 Hz, 2H), 6.09 (t, J=4.79 Hz, 1H), 7.32 (d, J=8.05 Hz, 1H), 7.60(d, J=15.6 Hz, 1H), 7.70 (d, J=8.36 Hz, 2H), 7.80 (s, 1H), 7.85 (d,J=8.12 Hz, 1H), 8.00 (d, J=1.77 Hz, 1H), 8.10 (d, J=8.36 Hz, 2H).

3,4-Dihydro-4,4-dimethyl-6-acetyl-1-(1,1-dimethylethyl)naphthalene(Compound D19)

To a solution of6-(2-methyl-1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthlen-1(2H)-one((Compound D15, 353 mg, 1.36 mmol) in 3 ml of dry ether at −78° C. wasadded dropwise t-BuLi (1 ml, 1.7 mmol, 1.7 M solution in pentane). Thisclear light a yellow solution was left at −78° C. for 30 min. Then,freshly distilled SOCl₂ (0.15 ml, 2.0 mmol) was added. The reactionmixture was stirred at −78° C. for additional 30 min and thereafterslowly warmed to room temperature. The reaction was quenched by additionof saturated NH₄Cl. The white solids were removed by filtration and theclear solution was concentrated to an oil, and purified by columnchromatography with ethyl acetate/hexane (1/10) to give the titlecompound as a yellow oil.

¹H NMR (CDCl₃): δ 7.92 (d, J=1.79 Hz, 1H), 7.76 (dd, J=1.80, 8.23 Hz,1H), 7.73 (d, J=8.23 Hz, 1H), 6.10 (t, J=4.98 Hz, 1H), 2.58 (s, 3H),2.18 (d, J=5.00 Hz, 2H), 1.34 (s, 9H), 1.25 (s, 6H).

(E)-4-[3-(3,4-Dihydro-4,4-dimethyl-1-(1,1-dimethyl-ethyl)naphth-6-yl)-prop-1-en-3-one]benzoicacid (Compound D20)

To a solution of3,4-dihydro-4,4-dimethyl-6-acetyl-1-(1,1-dimethylethyl)naphthalene(Compound D19, 60 mg, 0.234 mmol) and 4-carboxybenzaldehyde (35 mg,0.233 mmol) in 5 ml of EtOH and 1 ml of THF was added 3 ml of 1 Maqueous NaOH. The yellow reaction mixture was left overnight when itturned red and then quenched with 6% HCl until it became yellow again.The solvent was removed and the residue was dissolved in ethyl acetate.The organic solution was washed with brine and dried. After evaporationof the solvent, the residue was purified by recrystallization from ethylacetate to give 28 mg title compound as yellow crystals.

¹H NMR (CDCl₃): δ 8.15 (d, J=8.31 Hz, 2H), 8.00 (d, J=1.80 Hz, 1H), 7.86(dd, J=1.83, 8.24 Hz, 1H), 7.83 (d, J=15.82 Hz, 1H), 7.78 (d, J=8.48 Hz,1H), 7.74 (d, J=8.31 Hz, 2H), 7.65 (d, J=15.87 Hz, 1H), 6.13 (t, J=5.0Hz, 1H), 2.21 (d, J=4.9 Hz, 2H), 1.38 (s, 9H), 1.30 (s, 6H).

6-Bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound D21)

To a mixture of TiCl₃ (5 g, 32 mmol) of in 80 ml of dry DME under argonatmosphere was added in small portions lithium wire (0.80 g, 92 mmol).The reaction mixture was heated at 85° C. for 1 h and then cooled toroom temperature. To the above solution was added a mixture of6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H, 1.00g, 4.0 mmol) in 10 ml of dry DME and 10 ml of dry acetone through acannula. The resulting mixture was heated to reflux and was left for 12h and then cooled to room temperature. The reaction mixture was dilutedwith 80 ml of hexane and then filtered through florisil. Purification bycolumn chromatography with pure hexane as the eluent gave the titlecompound as a clear oil.

¹H NMR (CDCl₃): δ 1.23 (s, 6H), 1.60 t, J=7.09 Hz, 2H), 1.82 (s, 3H),1.92 (s, 3H), 2.49 (t, J=6.60 Hz, 2H), 7.10 (d, J=8.30 Hz, 1H), 7.26(dd, J=1.95, 6.05 Hz, 1H), 7.40 (d, J=2.08 Hz, 1H).

6-Acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound D22)

To a solution of6-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound D21, 910 mg, 3.3 mmol) andbis(triphenylphosphine)palladium(II) chloride (100 mg, 0.14 mmol) of in50 ml of DMF under argon was added (1-ethoxy vinyl)tributyl tin (1.713ml, 5.07 mmol). The resulting reaction mixture was heated at 85° C. for48 h and cooled down to room temperature. The reaction was quenched with15 ml of 10% HCl and then diluted with ethyl acetate. The organic layerwas washed with brine and dried over MgSO₄. Purification by columnchromatography with pure hexane afforded the title compound as a yellowoil (410 mg).

¹H NMR (CDCl₃): δ 1.28 (s, 6H), 1.64 (t, J=6.99 Hz, 2H), 1.86 (s, 3H),1.97 (s, 3H), 2.53 (t, J=6.6 Hz, 2H), 2.61 (s, 3H), 7.31 (d, J=8.06 Hz,1H), 7.74 (dd, J=1.96, 6.10 Hz, 1H), 7.92 (d, J=1.89 Hz, 1H).

(E)-4[3-{1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicacid (Compound D23)

The title compound can be obtained by following the procedure employedfor the preparation of(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D18).

(+/−)1-Hydroxy-6-(1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene(Compound D24)

To a solution of6-(1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15, 110 mg, 0.42 mmol) in 6 ml of EtOH at 0° C. was addedNaBH₄ (16 mg, 0.42 mmol). The reaction mixture was stirred for 4 h andkept in a freezer for overnight. The reaction was quenched with slowaddition of cold water and extracted with ethyl acetate. The organiclayer was dried and concentrated to an oil. Purification by columnchromatography with ethyl acetate/hexane (1/3) gave the title compoundas a clear oil.

¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.34 (s, 3H), 1.65 (s, 3H), 1.61 (m,1H), 1.89 (m, 2H), 2.07 (m, 1H), 3.74 (m, 2H), 4.05 (m, 2H), 4.74 (t,J=5.10 Hz, 1H), 7.30 (dd, J=1.65, 6.16, 1H), 7.41 (d, J=7.94 Hz, 1H),7.45 (d, J=1.83 Hz, 1H).

(+/−) 1-Hydroxy-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene(Compound D25)

A solution of1-hydroxy-6-(1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene(Compound D24, 54.9 mg, 0.21 mmol) in 3 ml of 10% HCl and 3 ml THF washeated at 100° C. for 1.5 h and cooled to room temperature. The reactionmixture was diluted with ethyl acetate and neutralized with sat. NaHCO₃.The organic layer was further washed with brine, dried and concentratedto an oil. Purification by column chromatography (silica) with ethylacetate/hexane (1/9) gave the title compound as a clear oil (24.8 mg).

¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.34 (s, 3H), 1.66 (m, 1H), 1.89 (m,2H), 2.10 (m, 1H), 2.56 (s, 3H), 4.75 (t, J=4.90, 1H), 7.54 (d, J=8.18Hz, 1H), 7.75 (dd, J=1.83, 6.29 Hz, 1H), 7.94 (d, J=1.77 Hz, 1H).

(+/−)1-(Methoxymethyloxy)-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene(Compound D26)

A solution of (+/−)1-hydroxy-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene (CompoundD25, 24.8 mg, 0.11 mmol), chloromethyl methyl ether (0.12 mmol),triethyl amine (0.02 ml, 0.13 mmol) and catalytic amount oftetrabutylammonium bromide in 2 ml of CH₂Cl₂ was stirred at roomtemperature for 5 h. Purification by column chromatography (silica) withethyl acetate/hexane (1/10) afforded the title compound as an oil (17.8mg).

¹H NMR (CDCl₃): δ 7.95 (d, J=1.7 Hz, 1H), 7.73 (dd, J=1.7, 8.4 Hz, 1H),7.44 (d, J=8.4 Hz, 1H), 4.88 (d, J=6.41 Hz, 1H), 4.76 (d, J=6.41 Hz,1H), 4.67 (m, 1H), 3.48 (s, 3H), 2.59 (s, 3H), 2.00 (m, 3H), 1.58 (m,1H), 1.37 (s, 3H), 1.29 (s, 3H).

(E)-4-[3-(1,2,3,4-Tetrahydro-4,4-dimethyl-1-(methoxymethyloxy)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D27)

The title compound can be prepared by following the procedure employedfor the preparation of(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D18).

6-Acetyl-1(2H)-(O-methyl oxime)-3,4-dihydro-4,4-dimethylnaphthalene(Compound D28)

To a solution of6-(1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15, 100 mg, 0.38 mmol), NaOAc (78.8 mg, 0.95 mmol) in 5 ml ofEtOH and 2 ml of THF was added methoxyamine hydrochloride (32.1 mg, 0.38mmol). The resulting mixture was stirred at room temperature forovernight. The solvent was removed and the residue was dissolved inethyl acetate (5 mL) and washed with saturated NaHCO₃, water and brine.The solvent was distilled off and the crude product was purified bycolumn chromatography with ethyl acetate/hexane (1/3) to give the titlecompound as an oil.

¹H NMR (CDCl₃): δ 1.42 (s, 6H), 2.03 (t, J=6.07 Hz, 2H), .2.24 (s, 3H),2.74 (t, J=6.71 Hz, 2H), 4.04 (s, 3H), 7.56 (dd, J=1.52, 6.72 Hz, 1H),7.70 (d, J=1.75 Hz, 1H), 8.02 (d, J=8.24 Hz, 1H).

(E)-4[3-{1(2H)-(O-methyloxime)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicacid (Compound D29)

The title compound can be prepared by following the procedure employedfor the preparation of(E)-4-[3-(3,4,dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D18).

3,4-dihydro-1-(trifluoromethylsulfonyl)oxy-4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D30)

To a cold solution (−78° C.) of 232.7 mg (1.267 mmol) of sodiumbis(trimethylsily)amide in 2.0 ml of THF was added a solution of 300.0mg (1.154 mmol) of6-(1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15) in 4.0 ml of THF. The reaction mixture was stirred at−78° C. for 30 minutes and then a solution of 498.0 mg (1.269 mmol) of5-chloro(2-bis-triflouromethylsulfonyl)imide in 3.0 ml of THF was added.After stirring at −78° C. for 1 hour, the solution was warmed to 0° C.and stirred for 12 hours. The reaction was quenched by the addition ofsaturated aqueous NH₄Cl. The mixture was extracted with EtOAc (50 ml)and the combined organic layers were washed with saturated aqueousNaHCO₃, water, and brine. The organic phase was dried over Na₂SO₄ andthen concentrated in vacuo to a yellow oil. Purification by columnchromatography (silica, 10% EtOAc-hexanes) yielded the title compound asa clear yellow oil.

¹H NMR (CDCl₃): δ_(—)7.43 (1H, s), 7.38 (2H, m), 5.95 (1H, t, J=4.8 Hz),4.07 (2H, m) 3.77 (2H, m) 2.42 (2H, d, J=4.9 Hz), 1.66 (3H, s), 1.32(6H, s).

3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D32)

A solution of 2-thienyllithium was prepared by the addition of 106.9 mg(0.67 ml, 1.67 mmol) of n-butyl lithium (2.5 M solution in hexanes) to acold solution (0° C.) of 140.0 mg (1.67 mmol) of thiophene in 1.0 ml ofTHF. After stirring for 3 h a solution of 364.0 mg (2.67 mmol) of zincchloride in 2.0 ml of THF was added. The resulting solution was warmedto room temperature, stirred for 30 minutes, and added via cannula to asolution of 262.0 mg (0.668 mmol) of3,4-dihydro-1-(trifluoromethylsulfonyl)oxy-4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D30) and 30 mg (0.03 mmol) oftetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF. The resultingsolution was heated at 50° C. for 12 h, cooled to room temperature anddiluted with saturated aqueous NH₄Cl. The mixture was extracted withEtOAc and the combined organic layers were washed with water and brine.The organic phase was dried over Na₂SO₄ and concentrated in vacuo to ayellow oil. Purification by column chromatography (10% EtOAc-hexanes)yielded the title compound as a yellow solid.

¹H NMR (CDCl₃): δ_(—)7.48 (1H, d, J=1.8 Hz), 7.34 (1H, d, J=7.9 Hz),7.28 (2H, m), 7.08 (2H, m), 6.18 (1H, t, J=4.8 Hz), 4.06 (2H, m), 3.82(2H, m), 2.34 (2H, d, J=4.8 Hz), 1.70 (3H, s), 1.34 (6H, s).

3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-acetylnaphthalene (CompoundD33)

A solution of3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D32, 103.0 mg, 0.32 mmol) in 4.0 mL THF and 4.0 mL 10% aqueousHCl was refluxed for 1.5 h. Upon cooling to room temperature, thereaction mixture was diluted with EtOAc and washed with water andsaturated aqueous NaCl. The organic layer was dried over MgSO₄ and thesolvents were removed under reduced pressure to give the title compoundas a colorless oil after column chromatography (10% EtOAc-hexanes).

¹H NMR (CDCl₃): δ 7.98 (1H, d, J=1.8 Hz), 7.75 (1H, dd, J=1.8, 8.1 Hz),7.46 (1H, d, J=8.1 Hz), 7.29 (1H, d, J=5.0 Hz), 7.09 (2H, m), 6.32 (1H,t, J=4.8 Hz), 2.61 (3H, s), 2.38 (2H, d, J=4.9 Hz), 1.38 (6H, s).

4-[3-oxo-3-(7,8-dihydro-5-(2-thienyl)-8,8-dimethyl-2-naphthalenyl)-1-propenyl]-BenzoicAcid (Compound D34)

To a solution of 62.6 mg (0.222 mmol)3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-acetylnaphthalene (CompoundD33) in 4.0 mL of MeOH were added 33.4 mg (0.222 mmol) of 4-carboxybenzaldehyde, and 240.0 mg (6.00 mmol; 2.0 mL of 3M aqueous NaOH). Theresulting solution was stirred at room temperature for 12 h,concentrated under reduced pressure, and the residual oil dissolved inEtOAc. The solution was treated with 10% HCl, and the organic layerwashed with H₂O, and saturated aqueous NaCl, before being dried overNa₂SO₄. Removal of the solvents under reduced pressure gave the titlecompound as a pale green solid after recrystallization from EtOH.

¹H NMR (acetone-d₆): δ_(—)8.16 (1H, s), 8.10 (1H, d, J=8.4 Hz), 8.00(5H, m), 7.84 (1H, d, J=15.5 Hz), 7.48 (2H, m), 7.14 (2H, m), 6.36 (1H,t, J=4.8 Hz), 2.83 (1H, s), 2.43 (2H, d, J=4.8 Hz), 1.39 (6H, s).

Methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate(Compound E2)

A degassed (with carbonmonoxide) solution of2-bromo-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one (Compound G),palladium(II)-bis(triphenylphosphine)chloride (277 mg, 0.4 mmol),1,3-bis(diphenylphosphino)-propane (325 mg, 0.8 mmol), DMSO (30 mL),methanol (15 mL) and triethylamine (15 mL) was placed in an oil bath(70° C.), under carbonmonoxide atmosphere) for 16 h. After dilution withwater the mixture was extracted with ethyl acetate. The organic layerwas washed with water, 10% HCl, saturated sodiumbicarbonate and brine.The organic layer was dried over MgSO₄, and the solvent was removed bydistillation. The residual crude material was purified by flashchromatography (silica, 1:4 ethyl acetate:hexane) to afford the titlecompound as a white solid.

¹HNMR (CDCl₃): δ 1.42 (s, 6H), 2.05 (t, J=6.6 Hz, 2H), 2.77 (dd, J=6.6,2H), 3.93 (s, 3H), 7.52 (d, J=8.3 Hz, 1H), 8.17 (dd, J=1.8, 8.3 Hz, 1H),8.67 (d, J=1.8 Hz, 1H).

5,5-Dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylic acid(Compound E3)

To a solution ofmethyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate(Compound E2, 1.05 g, 4.5 mmol) in 10 mL of ethanol and TBF (10 mL) wasadded sodiumhydroxide 9 mL (1M solution). The solution was stirred for16 h and thereafter acidified with 10% HCl. The mixture was extractedwith ethyl acetate, the combined organic layer was washed with water andbrine, and dried over MgSO4. The solvent was distilled off under reducedpressure to afford the title compound as a white solid.

¹HNMR (Acetone-D6): δ 1.44 (s, 6H), 2.07 (t, J=6.7 Hz, 2H), 2.73 (t,J=6.7 Hz, 2H), 7.70 (d, J=8.2 Hz, 1H), 8.19 (dd, J=1.9, 8.2 Hz, 1H),8.57 (d, J=1.9 Hz, 1H).

Methyl 5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate (Compound E4)

To a solution of sodium bis(trimethylsilyl)amide (550.1 mg, 3.00 mmol,3.0 mL of a 1.0 M solution in THF) in 5.0 mL of THF at −78° C. was added620.0 mg (2.67 mmol) ofmethyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate(Compound E2) in 8.0 mL of THF. After 30 min a solution of 1.15 g (2.94mmol) of 2-N,N-bis(trifluoromethylsulfonyl)amino-5-chloropyridine in 6.0mL of THF was added. Stirring for 45 min at −78° C. was followed bywarming to room temperature and stirring for 5 h. The reaction wasquenched by the addition of saturated aqueous NH₄Cl and extracted withEtOAc. The combined organic layers were washed with 5% aqueous NaOH anddried over MgSO₄. Concentration of the dry solution under reducedpressure to an oil and column chromatography using 10% EtOAc-hexanesafforded the title compound as a yellow oil.

¹H NMR(CDCl₃): δ 1.33 (s,6H), 2.45 (d, J=4.8 Hz, 2H), 3.93 (s, 3H), 6.03(t, J=4.8 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 8.00 (m, 2H).

Methyl 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylate(Compound E5)

To a solution of 329.0 mg (3.93 mmol) of thiophene in 2.0 mL THF at 0°C. was added 251.8 mg (3.93 mmol, 1.56 mL of 2.5 M solution in hexanes)of n-butyllithium. After stirring for 3 h at 0° C., a solution of 845.0mg (6.28 mmol) of ZnCl₂ in 5.0 mL THF was added and the resultingsolution stirred for 30 minutes. This solution was added to a secondflask containing 570.0 mg (1.57 mmol) of methyl5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate(Compound E4) and 76.0 mg (0.063 mmol) oftetrakis(triphenyphosphine)palladium(0) in 4.0 mL THF, and the resultingsolution was heated to 50° C. for 3 h. Upon cooling to room temperaturethe reaction was quenched by the addition of saturated aqueous NH₄Cl.Extraction with EtOAc was followed by washing of the combined organiclayers with H₂O and saturated aqueous NaCl, and drying over MgSO₄. Thedry solution was concentrated under reduced pressure and the titlecompound was isolated from the residue as a yellow oil by columnchromatography (5-10% EtOAc/hexanes).

¹H NMR(CDCl₃): δ 1.34 (s, 6H), 2.35 (d, J=4.9 Hz, 2H), 3.86 (s, 3H),6.23 (t, J=4.9 Hz, 1H), 7.06 (m, 2H), 7.28 (m, 1H), 7.43 (d, J=8.0 Hz,1H), 7.92 (dd, J=1.7, 8.0 Hz, 1H), 8.06 (d, J=1.7 Hz, 1H).

5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6)

To a solution of methyl5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-2-naphthalenecarboxylate(Compound E5, 430.0 mg, 1.44 mmol) in 3.0 mL of EtOH and 3.0 mL THF wasadded NaOH (240.0 mg, 6.00 mmol; 3.0 mL of a 2N aqueous solution). Theresulting solution was warmed to 35° C. for 6 h, cooled to roomtemperature and quenched with 1M HCl. The mixture was extracted withEtOAc and the combined organic layers washed with H₂O and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure afforded the title compound as a pale yellowsolid.

¹H NMR(CDCl₃) Î 1.34 (s, 6H), 2.38 (d, J=4.8 Hz, 2H), 6.25 t, J=4.8 Hz,1H), 7.12 (m. 3H), 7.45 (dd, J=1.8, 4.7 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H),7.92 (dd, J=1.8, 8.0 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H).

Ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E7)

A solution of5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6, 180.0 mg, 0.638 mmol), ethyl 4-aminobenzoate (137.0 mg,0.829 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(160.0 mg, 0.829 mmol), and 4-N,N-dimethylaminopyridine (101.0 mg, 0.829mmol) in 6.0 mL DMF was stirred overnight at room temperature. EtOAc(100 mL) was added and the solution washed with H₂O, 5% HCl, saturatedaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the sovents under reduced pressure and columnchromatography (10-25% EtOAc-hexanes) of the residual oil afforded thetitle compound as a colorless solid.

¹H NMR(CDCl₃): δ 1.36 (s, 6H), 1.39 (t, J=7.1 Hz, 3H), 2.38 (d, J=4.8Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 6.27 (t, J=4.8 Hz, 1H), 7.09 (m, 2H),7.29 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.76 (dd,J=1.9, 8.0 Hz, 1H), 7.83 (s, 1H), 7.88 (d, J=1.9 Hz, 1H), 8.03 (d, J=8.8Hz, 2H).

4-[[(5,5-Dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-BenzoicAcid (Compound E8)

To a solution of ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E7, 110.0 mg, 0.255 mmol) in 2.0 mL of EtOH and 1.0 mL THF wasadded NaOH (80.0 mg, 2.00 mmol; 2.0 mL of a 1N aqueous solution). Afterstirring overnight at room temperature the reaction was quenched by theaddition of 1M aqueous HCl. The mixture was extracted with EtOAc and thecombined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over MgSO₄. Removal of the solvents under pressureafforded the title compound as a pale yellow solid.

¹H NMR(acetone-d₆): δ 1.34 (s, 6H), 2.38 (d, J=4.9 Hz, 2H), 6.27 (t,J=4.9 Hz, 1H), 7.12 (m, 2H), 7.44 (dd, J=1.3, 5.0 Hz, 1H), 7.55 (d,J=8.0 Hz, 1H), 7.88 (m. 3H), 8.02-7.91 (m, 3H), 9.75 (s, 1H).

Ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E9)

A solution of5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6, 50.0 mg, 0.177 mmol), ethyl 4-hydroxybenzoate (38.2 mg,0.230 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(44.0 mg, 0.230 mmol), and 4-N,N-dimethylaminopyridine (28.0 mg, 0.230mmol) in 2.0 mL DMF was stirred overnight at room temperature. EtOAc (50mL) was added and the solution washed with H₂O, 5% HCl, saturatedaqueous NaCO₃, and saturated aqueous NaCl before being dried over MgSO₄.Removal of the sovents under reduced pressure and column chromatography(10% EtOAc-hexanes) of the residual oil afforded the title compound as acolorless solid.

¹H NMR(CDCl₃): δ 1.36 (s, 6H), 1.39 (t, J=7.2 Hz, 3H), 2.39 (d, J=4.9Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 6.26 (t, J=4.9 Hz, 1H), 7.09 (m, 2H),7.25 (m, 2H), 7.49 (d, J=8.2 Hz, 11H), 8.08 (m, 3H), 8.22(d, J=1.8 Hz,1H).

2-trimethylsilylethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E10)

A solution of5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6, 79.0 mg, 0.280 mmol), 2-trimethylsilylethyl4-hydroxybenzoate (73.3 mg, 0.308 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg,0.364 mmol), and 4-N,N-dimethylaminopyridine (44.5 mg, 0.364 mmol) in2.0 mL DMF was stirred overnight at room temperature. Et₂O (100 mL) wasadded and the solution washed with H₂O, 5% HCl, saturated aqueous NaCO₃,and saturated aqueous NaCl before being dried over MgSO₄. Removal of thesovents under reduced pressure and column chromatography (10%EtOAc-hexanes) of the residual oil afforded the title compound as acolorless solid.

¹H NMR(CDCl₃): δ 0.10 (s, 9H), 1.15 (t, J=8.2 Hz, 2H), 1.38 (s, 6H),2.39 (d, J=4.0 Hz, 2H), 4.43 (t, J=8.2 Hz, 2H), 6.28 (t, J=4.0 Hz, 1H),7.09 (m, 2H), 7.26 (m, 3H), 7.52 (d, J=7.2 Hz, 1H), 8.09 (m, 3H), 8.22(s, 1H).

4-[[(5,5-Dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoicacid (Compound E11)

To a solution of 2-trimethylsilylethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E10, 100.0 mg, 0.198 mmol) in 2.0 mL THF at room temperaturewas added 155.3 mg of tetrabutylammonium fluoride (0.594 mmol 0.6 mL ofa 1M solution in THF). After stirring overnight the reaction was dilutedwith EtOAc and washed with H₂O and saturated aqueous NaCl before beingdried over MgSO₄. The solvents were removed under reduced pressure andthe residue washed with hot acetonitrile leaving the product as acolorless solid.

¹H NMR(acetone-d₆): δ 1.37 (s, 6H), 2.42 (d, J=4.8 Hz, 2H), 6.30 (t,J=4.8 Hz, 1H), 7.14 (m, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.44 (dd, J=1.1,5.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 8.12 (m, 4H).

1(2H)-(Propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene-7-carboxylicacid (Compound E12)

To a cold (−78° C.) solution of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37, 640.0 mg, 2.30 mmol) in 20 mL THF was addedt-butyllithium (294.7 mg, 4.60 mmol; 2.7 mL of a 1.7M solution inpentane). After 1 h dry CO₂ gas was bubbled through the solution for 1h. The resulting mixture was allowed to warm to room temperature andthen quenched with 10% aqueous HCl. The mixture was extracted with EtOAcand the combined organic layers washed with H₂O and saturated aqueousNaCl before being dried over Na₂SO₄. Concentration of the dry solutionunder reduced pressure and washing of the residue with hexanes affordedthe title compound as a pale yellow solid.

¹H NMR(acetone-d₆): δ 1.25 (s, 6H), 1.63 (t, J=6.9 Hz, 2H), 1.85 (s,3H), 1.95 (s, 3H), 2.53 (t, J=6.9 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.82(dd, J=1.8, 8.1 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H).

2-(Trimethylsilyl)ethyl-4-[{(5,5-dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E13)

A solution of 5,5-dimethyl-5,6-dihydro-8(7H)-(1-propyliden-2-yl)-naphthalene-2-carboxylic acid (Compound E12,70.0 mg, 0.287 mmol), 2-trimethylsilylethyl 4-hydroxybenzoate (71.0 mg,0.298 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(71.0 mg, 0.370 mmol), and 4-N,N-dimethylaminopyridine (45.0 mg, 0.370mmol) in 2.0 mL DMF was stirred overnight at room temperature. Et₂O (100mL) was added and the solution washed with H₂O, 5% HCl, saturatedaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure and columnchromatography (5% EtOAc-hexanes) of the residual oil afforded the titlecompound as a colorless oil.

¹H NMR(CDCl₃): δ 0.09 (s, 9H), 1.14 (t, J=8.4 Hz, 2H), 1.28 (s, 6H),1.66 (d, J=6.9 Hz, 2H), 1.86 (s, 3H), 2.00 (s, 3H), 2.54 (t, J=6.9 Hz,2H), 4.30 (t, J=8.4 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.1 Hz,1H), 7.97 (dd, J=1.9, 8.1 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 8.11 (d,J=8.7 Hz, 2H).

4-[{(5,5-Dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)carbonyl}oxy]benzoicacid (Compound E14)

To a solution of 2-trimethylsilylethyl4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-(propyliden-2-yl)-2-naphthalenyl)carbonyl]oxy]-benzoate(Compound E13, 84.0 mg, 0.181 mmol) in 2.0 mL THF at 0° C. was added130.7 mg of tetrabutylammonium fluoride (0.50 mmol; 0.5 mL of a 1Msolution in THF). After stirring at 0° C. for 1.5 h and at roomtemperature for 4.5 h, the reaction was diluted with EtOAc and washedwith H₂O and saturated aqueous NaCl before being dried over MgSO₄. Thesolvents were removed under reduced pressure and the residue crystalizedfrom CH₃CN to give the product as a colorless solid.

¹H NMR(acetone-d6): δ 1.29 (s, 6H), 1.67 (t, J=6.9 Hz, 2H), 1.87 (s,3H), 1.99 (s, 3H), 2.56 (t, J=6.9 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.54(d, J=8.2 Hz, 1H), 7.97 (dd, J=1.9, 8.2 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H),8.14 (d, J=8.7 Hz, 2H).

Ethyl4-[{(5,5-dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E15)

A solution of5,5-dimethyl-5,6-dihydro-8(7H)-(propyliden-2-yl)-2-naphthalenecarboxylicacid (Compound E12, 31.0 mg, 0.127 mmol), ethyl 4-hydroxybenzoate (27.4mg, 0.165 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (31.6 mg, 0.165 mmol), and 4-N,N-dimethylaminopyridine(20.2 mg, 0.165 mmol) in 2.0 mL DMF was stirred overnight at roomtemperature. EtOAc (50 mL) was added and the solution washed with H₂O,5% HCl, saturated aqueous NaCO₃, and saturated aqueous NaCl before beingdried over MgSO₄. Removal of the solvents under reduced pressure andcolumn chromatography (5% EtOAc-hexanes) of the residual oil affordedthe title compound as a colorless oil.

¹H NMR(CDCl₃): δ 1.28 (s, 6H), 1.41 (t, J=7.1 Hz, 2H), 1.66 (t, t J=6.9Hz, 2H), 1.86 (s, 3H), 2.00 (s, 3H), 2.56 (t, J=6.9 Hz, 2H), 4.40 (q,J=7.1 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.98 (dd,J=1.8, 8.1 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H).

Ethyl4-[(5,5-dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoate(Compound E16)

A solution of1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene-7-carboxylicacid (Compound E12, 100.0 mg, 0.410 mmol), ethyl 4-aminobenzoate (81.0mg, 0.490 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (117.0 mg, 0.615 mmol), and 4-N,N-dimethylaminopyridine(61.0 mg, 0.500 mmol) in 3.0 mL DMF was stirred overnight at roomtemperature. EtOAc (100 mL) was added and the solution washed with H₂O,10% HCl, saturated aqueous NaCO₃, and saturated aqueous NaCl beforebeing dried over MgSO₄. Removal of the solvents under reduced pressureand column chromatography (10-15% EtOAc-hexanes) of the residual oilafforded the title compound as a colorless solid.

¹H NMR(CDCl₃): δ 1.29 (s, 6H), 1.40 (t, J=7.1 Hz, 2H), 1.64 (t, J=7.0Hz, 2H), 1.86 (s, 3H), 2.00 (s, 3H), 2.52 (t, J=6.6 Hz, 2H), 4.37 (q,J=7.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 1H), 7.63 (dd, J=1.8, 8.1 Hz, 1H),7.73 (d, J=8.6 Hz, 2H), 7.75 (d, J=1.8 Hz, 1H), 7.92 (s, 1H), 8.06 (d,J=8.6 Hz, 2H).

4-[(5,5-Dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoicacid (Compound E17)

To a solution of ethyl4-[(5,5-dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoate(Compound E16, 25.0 mg, 0.064 mmol) in 3.0 mL of EtOH and 3.0 mL THF wasadded NaOH (80.0 mg, 2.00 mmol; 2.0 mL of a 1N aqueous solution). Afterstirring overnight at room temperature the reaction was quenched by theaddition of 10% aqueous HCl. The mixture was extracted with EtOAc andthe combined organic layers were washed with H₂O and saturated aqueousNaCl and thereafter dried over Na₂SO₄. Removal of the solvents underpressure and crystallization from CH₃CN afforded the title compound as acolorless solid.

¹H NMR(acetone-d₆): δ 1.25 (s, 6H), 1.64 (t, J=6.9 Hz, 2H), 1.85 (s,3H), 1.96 (s, 3H), 2.55 (t, J=6.9 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.78(dd, J=1.9, 8.1 Hz, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.95-8.05 (m, 4H), 9.71(s, 1H).

Methyl-5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylate(Compound E18)

To a solution ofmethyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate(Compound E2, 835.0 mg, 3.60 mmol) in 25.0 mL of THF at room temperaturewas added TiCl₄ (670.0 mg, 3.55 mmol). Thereafter a solution ofthiophenol (430.0 mg, 3.90 mmol) and Et₃N (730.0 mg, 7.20 mmol) in 10 mLTHF was added. The resulting brown mixture was stirred for 6 h beforeH₂O was carefully added to quench the reaction. The product wasextracted into Et₂O and the combined organic layers washed withsaturated aqueous NaCl and dried over MgSO₄. Removal of the solventsunder reduced pressure afforded a solid from which the title compoundwas isolated as a yellow solid by column chromatography (5%EtOAc-hexanes).

¹H NMR (CDCl₃): δ 1.34 (s, 6H), 2.40 (d, J=4.7 Hz, 2H), 3.85 (s, 3H),6.51 (t, J=4.7 Hz, 1H), 7.10-7.36 (m, 5H), 7.38 (d, J=8.1 Hz, 1H), 7.88(dd, J=1.8, 8.0 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H).

5,5-Dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid(Compound E19)

To a solution of methyl5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylate(Compound E18, 300.0 mg, 0.926 mmol) in 4.0 mL of EtOH and 2.0 mL THFwas added NaOH (200.0 mg, 5.00 mmol; 5.0 mL of a 1N aqueous solution).After stirring overnight at room temperature the reaction was quenchedby the addition of 10% aqueous HCl. The mixture was extracted with EtOAcand the combined organic layers washed with H₂O and saturated aqueousNaCl before being dried over Na₂SO₄. Removal of the solvents underpressure afforded the title compound as a yellow solid.

¹H NMR(CDCl₃): δ 1.35 (s, 6H), 2.41 (d, J=4.6 Hz, 2H), 6.54 (t, J=4.6Hz, 1H), 7.10-7.34 (m, 5H), 7.40 (d, J=8.1 Hz, 1H), 7.92 (dd, J=1.8, 8.1Hz), 8.36 (d, J=1.8 Hz, 1H).

Ethyl4-[(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoate(Compound E20)

A solution of5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid(Compound E19, 183.0 mg, 0.580 mmol), ethyl 4-aminobenzoate (107.0 mg,0.650 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(144.0 mg, 0.750 mmol), and 4-dimethylaminopyridine (85.0 mg, 0.700mmol) in 5.0 mL DMF was stirred overnight at room temperature. EtOAc(100 mL) was added and the solution washed with H₂O and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure and column chromatography (20% EtOAc-hexanes) ofthe residual oil afforded the title compound as a colorless solid.

¹H NMR(CDCl₃): δ 1.37 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.45 (d, J=4.7Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.65 (t, J=4.7 Hz, 1H), 7.17-7.35 (m,5H), 7.45 (d, J=8.1 Hz, 1H), 7.52 (s, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.77(dd, J=1.8, 8.1 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.7 Hz, 2H).

4-[(5,5-Dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E21)

To a solution of ethyl4-[(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoate(Compound E20, 90.0 mg, 0.196 mmol) in 3.0 mL of EtOH and 3.0 mL THF wasadded NaOH (120.0 mg, 3.00 mmol; 3.0 mL of a 1N aqueous solution). Afterstirring overnight at room temperature the reaction was quenched by theaddition of 10% aqueous HCl. The mixture was extracted with EtOAc andthe combined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over Na₂SO₄. Removal of the solvents under pressureafforded the title compound as a pale yellow solid.

¹H NMR(acetone-d₆): δ 1.36 (s, 6H), 2.46 (d, J=4.7 Hz, 2H), 6.11 (t,J=4.7 Hz, 1H), 7.13-7.36 (m, 5H), 7.51 (d, J=8.0 Hz, 1H), 7.85 (dd,J=1.9, 8.0 Hz, 1H), 7.91-8.03 (m, 4H), 8.24 (d, J=1.9 Hz, 1H), 9.67 (s,1H).

4-[(5,5-Dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E22)

To a solution of4-[(5,5-dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E21, 60.0 mg, 0.140 mmol) in 6.0 mL Et₂O, 3.0 mL CH₂Cl₂,and 2.0 mL THF at 0° C. was added m-chloroperbenzoic acid (57-80%)(74-110 mg, 0.430-0.640 mmol). The resulting solution was warmed to roomtemperature and stirred overnight. Water was added and the mixtureextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried over Na₂SO₄. Removal ofthe solvents under reduced pressure and crystallization of the residuefrom CH₃CN afforded the title compound as a colorless solid.

¹H NMR (acetone-d₆): δ 1.23 (s, 6H), 2.60 (d, J=4.9 Hz, 2H), 7.51-7.62(m, 5H), 7.89 (dd, J=1.8, 7.9 Hz, 1H), 7.94 (s, 1H), 7.95-8.06 (m, 6H),8.61 (d, J=1.9 Hz, 1H).

Ethyl4-[{(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E23)

A solution of5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid(Compound E19, 150.0 mg, 0.484 mmol), ethyl 4-hydroxybenzoate (88.5 mg,0.530 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(120.6 mg, 0.630 mmol), and 4-N,N-dimethylaminopyridine (77.0 mg, 0.630mmol) in 5.0 mL DMF was stirred overnight at room temperature. EtOAc (50mL) was added and the solution washed with H₂O and saturated aqueousNaCl before being dried over MgSO₄. Removal of the solvents underreduced pressure and column chromatography (10-15% EtOAc-hexanes) of theresidual oil afforded the title compound as a colorless solid.

¹H NMR(CDCl₃): δ 1.37(s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.44 (d, J=4.8 Hz,2H), 4.39 (q, J=7.1 Hz, 2H), 6.57 (t, J=4.8 Hz, 1H), 7.15-7.36 (m, 7H),7.45 (d, J=8.1 Hz, 1H), 8.01 (dd, J=1.8, 81 Hz, 1H), 8.10 (d, J=8.7 Hz,2H), 8.44 (d, J=1.8 Hz, 1H).

Ethyl4-[{(5,5-dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E24)

A solution of ethyl4-[{(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E23, 50.0 mg, 0.109 mmol) in 5.0 mL Et₂O at 0° C. was addedm-chloroperbenzoic acid (50%) (25 mg, 0.145 mmol). The resultingsolution was warmed to room temperature and stirred overnight. Et₂O wasadded and the organic layer washed with H₂O, saturated aqueous NaHCO₃,and saturated aqueous NaCl before being dried over Na₂SO₄. Removal ofthe solvents under reduced pressure and and column chromatography (20%EtOAc-hexanes) afforded the title compound as a colorless solid.

¹H NMR (CDCl₃): δ 1.27 (s, 6H), 1.42 (t, J=7.1 Hz, 3H), 2.56 (d, J=4.9Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 7.43-7.57 (m,5H), 8.02 (m, 3H), 8.14 (d, J=8.7 Hz, 2H), 8.68 (d, J=1.7 Hz, 1H).

2-(Trimethylsilyl)ethyl4-[{(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E25)

A solution of5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid(Compound E19, 170.0 mg, 0.548 mmol), 2-trimethylsilylethyl4-hydroxybenzoate (130.0 mg, 0.548 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126.0 mg,0.657 mmol), and 4-N,N-dimethylaminopyridine (74.0 mg, 0.600 mmol) in4.0 mL DMF was stirred overnight at room temperature. EtOAc (100 mL) wasadded and the solution washed with H₂O, 10% HCl, and saturated aqueousNaCl before being dried over MgSO₄. Removal of the solvents underreduced pressure and column chromatography (5% EtOAc-hexanes) of theresidual oil afforded the title compound as a colorless oil.

¹H NMR(CDCl₃): δ 0.10 (s, 9H), 1.15 (t, J=8.4 Hz, 2H), 1.38 (s, 6H),2.44 (d, J=4.7 Hz, 2H), 4.43 (d, J=8.4 Hz, 2H), 6.58 (t, J=4.7 Hz, 1H),7.16-7.36 (m, 7H), 7.45 (d, J=8.1 Hz, 1H), 8.02 (dd, J=1.8, 8.1 Hz, 1H),8.10 (d, J=8.7 Hz, 2H), 8.45 (d, J=1.8 Hz, 1H).

4-[{(5,5-Dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoicacid (Compound E26)

To a solution of 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E25, 200.0 mg, 0.377 mmol) in 2.0 mL THF at 0° C. was addedtetrabutylammonium fluoride (295,5 mg, 1.13 mmol; 1.13 mL of a 1Msolutution in THF). After 2 h the solution was warmed to roomtemperature and stirred overnight. EtOAc was added and the organic layerwashed with H₂O and saturated aqueous NaCl. Removal of the solventsunder reduced pressure and recrystallization of the residue from CH₃CNafforded the title compound as a pale yellow solid.

¹H NMR(acetone-d₆): δ 1.39 (s, 6H), 2.51 (d, J=4.7 Hz, 2H), 6.67 (t,J=4.7 Hz, 1H), 7.19-7.38 (m, 6H), 7.61 (d, J=8.1 Hz, 1H), 8.02 (dd,J=1.8, 8.1 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.43 (d, J=8.1 Hz, 1H).

4-[{(5,5-Dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoicacid (Compound E27)

To a solution of4-[[(5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalen-2-yl)carbonyl]oxy]-benzoicacid (Compound E26, 50.0 mg, 0.116 mmol) in 3.0 mL CH₂Cl₂, and 1.0 mLTHF at 0° C. was added m-chloroperbenzoic acid (57-80%) (34-52 mg,0.197-0.299 mmol). The resulting solution was warmed to room temperatureand stirred overnight. Water was added and the mixture extracted withEtOAc. The combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried over Na₂SO₄. Removal of the solventsunder reduced pressure and crystallization of the residue from CH₃CNafforded the title compound as a colorless solid.

¹H NMR (acetone-d₆): δ 1.27 (s, 6H), 2.65 (d, J=4.8 Hz, 2H), 7.14 (d,J=8.7 Hz, 2H), 7.57-7.68 (m, 5H), 8.03 (m, 3H), 8.17 (d, J=8.7 Hz, 2H),8.77 (d, J=1.8 Hz, 1H).

Ethyl4-[(5,5-Dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E28)

To a solution of5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalene-2-carboxylic acid(Compound E3, 400.0 mg, 1.833 mmol), ethyl 4-aminobenzoate (317.8 mg,1.924 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(386.5 mg, 2.016 mmol), and 4-dimethylaminopyridine (246.3 mg, 2.016mmol) in 18.0 mL CH₂Cl₂ was stirred at room temperature for 2 h. EtOAc(25 mL) was added and the solution washed with H₂O, 1M HCl, andsaturated aqueous NaCl before being dried over MgSO₄. Removal of thesolvents under reduced pressure and column chromatography (30%EtOAc-hexanes) of the residue afforded the title compound as a colorlesssolid.

¹H NMR(CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 1.45 (s, 6H), 2.08 (t, J=7.1Hz, 2H), 2.80 (t, J=6.6 Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 7.62 (d, J=8.3Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 8.09 (d, J=8.6 Hz, 2H), 8.14 (bs, 1H),8.21 (dd, J=2.1, 8.3 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H).

4-[(5,5-Dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E29)

A solution of ethyl4-[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E28, 50.0 mg, 0.137 mmol) and NaOH (54.7 mg, 1.37 mmol; 0.68mL of a 2N aqueous solution) in 2.0 mL EtOH and 1.0 mL THF was stirredat room temperature overnight. The reaction mixture was acidified with10% HCl and extracted with EtOAc. The combined organic layers werewashed with H₂O and saturated aqueous NaCl before being dried overNa₂SO₄. Removal of the solvents under reduced pressure andcrystallization of the residual solid from MeOH/H₂O afforded the titlecompound as yellow crystals.

¹H NMR (DMSO-d₆): δ 1.40 (s, 6H), 2.01 (t, J=6.7 Hz, 2H), 2.74 (t, J=7.0Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.93 (m, 4H), 8.16 (dd, J=2.1, 8.3 Hz,1H), 8.45 (d, J=2.0 Hz, 1H), 10.68 (s, 1H), 12.75 (bs, 1H).

Ethyl4-[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E30)

A mixture of ethyl4-[(5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalen-2-yl)carboxamido]-benzoate(Compound E28, 100.0 mg, 0.274 mmol), O-methylhydroxylaminehydrochloride (25.1 mg, 0.301 mmol), and NaOAc)3H₂O (81.9 mg, 0.602mmol) in 3.0 mL of EtOH was heated to 65° C. for 3 h and then stirred atroom temperature for 68 h. The reaction was diluted with H₂O andextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried over MgSO₄. Removal of thesolvents under reduced pressure and column chromatography (20-30%EtOAc-hexanes) of the residue afforded the title compound as a colorlesssolid.

¹H NMR (CDCl₃): δ 1.32 (s, 6H), 1.40 (t, J=7.2 Hz, 2H), 1.75 (t, J=7.0Hz, 2H), 2.81 (t, J=7.0 Hz, 2H), 4.04 (s, 3H), 4.37 (q, J=7.1 Hz, 2H),7.49 (d, J=8.2 Hz, 1H), 7.76 (dd, J=1.9, 8.7 Hz, 2H), 7.88 (dd, J=2.1,8.3 Hz, 1H), 8.06 (dd, J=1.7, 8.7 Hz, 2H), 8.12 (bs, 1H), 8.40 (d, J=2.0Hz, 1H).

4-[(5,5-Dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E31)

A solution of ethyl(E)-4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)carboxamido]-benzoate(Compound E30, 31.4 mg, 0.080 mmol) and NaOH (31.8 mg, 0.796 mmol; 0.40mL of a 2N aqueous solution) in 2 mL EtOH was stirred at roomtemperature overnight. The reaction was acidified with 10% HCL andextracted with EtOAc. The combined organic layers were dried (Na₂SO₄)and concentrated under reduced pressure to give an off-white solid.Crystallization from Et₂O afforded the title compound as a colorlesssolid.

¹H NMR (DMSO-d₆): δ 1.27 (s, 6H), 1.69 (t, J=6.9 Hz, 2H), 2.74 (t, J=6.9Hz, 2H), 3.96 (s, 3H), 7.58 (d, J=8.3 Hz, 1H), 7.90 (m, 5H), 8.36 (d,J=2.0 Hz, 1H), 10.57 (s, 1H), 12.73 (bs, 1H).

(+/−) Ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E32)

A solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalen-2-yl)carboxamido]-benzoate(Compound E28, 125.0 mg, 0.342 mmol) in 2.0 mL EtOH and 2.0 mL THF wascooled to 0° C. and treated with NaBH₄ (11.5 mg, 0.304 mmol). After 4 hthe reaction was quenched by the careful addition of H₂O, followed by0.5 mL 1M HCl. EtOAc (25 mL) was added and the solution washed with 1MHCl, dilute aqueous NaHCO₃, H₂O and saturated aqueous NaCl before beingdried over Na₂SO₄. Removal of the solvents under reduced pressureafforded the title compound as a colorless solid.

¹H NMR (acetone-d₆): δ 1.28 (s, 3H), 1.31 (s, 3H), 1.35 (t, J=7.2 Hz,3H), 1.65 (m, 1H), 1.88 (m, 3H), 4.32 (q, J=7.1 Hz, 2H), 4.69 (q, J=5.8Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.83 (dd, J=2.2, 8.3 Hz, 1H), 7.99 (s,4H), 8.09 (d, J=1.9 Hz, 1H), 9.81 (bs, 1H).

(+/−)4-[(5,5-Dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E33)

A mixture of (+/−) ethyl-4-[(S,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-yl)carboxamido]-benzoate(Compound E32, 50.0 mg, 0.136 mmol) and NaOH (54.4 mg, 1.36 mmol; 0.68mL of a 2N aqueous solution) in 3 mL EtOH was stirred at roomtemperature for 19 h. The resulting solution was acidified with 10% HCland extracted with EtOAc. The combined organic layers were washed withH₂O and saturated aqueous NaCl, and then dried over Na₂SO₄. Removal ofthe solvents under reduced pressure afforded the title compound as acolorless solid.

¹H NMR (DMSO-d₆): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.61 (m, 1H), 1.80 (m,2H), 1.95 (m, 1H), 4.87 (m, 1H), 5.30 (bs, 1H), 7.49 (d, J=8.2 Hz, 1H),7.78 (dd, J=1.9, 8.2 Hz, 1H), 7.49 (s, 4H), 8.01 (s, 1H), 10.47 (s, 1H),12.72 (bs, 1H).

(+/−) Ethyl4-[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E34)

To a solution of (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E32, 57.0 mg, 0.155 mmol) in 5.0 mL CH₂Cl₂ at 0° C. was addeddiisopropylethyl amine (276.2 mg, 2.137 mmol), chloromethyl methyl ether(37.7 mg, 0.469 mmol), and a catalytic amount of tetrabutylammoniumiodide. The resulting solution was stirred at 45° C. overnight. Uponcooling to room temperature the solution was diluted with EtOAc andwashed with 5% HCl, H₂O, saturated aqueous NaHCO₃, and saturated aqueousNaCl, before being dried over MgSO₄. Removal of the solvents underreduced pressure, followed by column chromatography (15% EtOAc-hexanes)afforded the title compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.27 (s, 3H), 1.35 (s, 3H), 1.39 (t, J=7.1 Hz, 3H),1.64 (m, 1H), 1.90-2.13 (m, 3H), 3.48 (s, 3H), 4.36 (q, J=7.1 Hz, 2H),4.67 (t, J=5.0 Hz, 1H), 4.79 (d, J=6.9 Hz, 1H), 4.89 (d, J=6.9 Hz, 1H),7.43 (d, J=8.2 Hz, 1H), 7.74 (m, 3H), 7.88 (d, J=2.0 Hz, 1H), 8.03 (d,J=8.7 Hz, 2H), 8.18 (s, 1H).

(+/−)4-[(5,5-Dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E35)

A mixture of(+/−) ethyl4-[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E34, 30.0 mg, 0.073 mmol) and NaOH (40.0 mg, 1.00 mmol; 1.0 mLof a 1N aqueous solution) in 1.0 mL EtOH and 1.0 mL THF was stirred atroom temperature overnight. The resulting solution was acidified with10% HCl and extracted with EtOAc. The combined organic layers werewashed with H₂O and saturated aqueous NaCl, and then dried over Na₂SO₄.Removal of the solvents under reduced pressure afforded the titlecompound as a colorless oil.

¹H NMR (acetone-d₆): δ 1.27 (s, 3H), 1.34 (s, 3H), 1.65 (m, 1H), 1.95(m, 2H), 2.08 (m, 1H), 3.42 (s, 3H), 4.66 (t, J=5.0 Hz, 1H), 4.77 (d,J=6.9 Hz, 1h), 4.84 (d, J=6.9 Hz, 1h), 7.53 (d, J=8.2 Hz, 1H), 7.86 (dd,J=2.0, 8.2 Hz, 1H), 8.00 (m, 5H), 9.78 (s, 1H).

2-(Trimethylsilyl)ethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E36)

To a solution of5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalene-2-carboxylic acid(Compound E3, 154.0 mg, 0.706 mmol), 2-(trimethylsilyl)ethyl4-hydroxybenzoate (185.0 mg, 0.777 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (176.0 mg,0.918 mmol), and 4-dimethylaminopyridine (112.2 mg, 0.918 mmol) in 4.0mL DMF was stirred at room temperature overnight. EtOAc (100 mL) wasadded and the solution washed with H₂O, 1M HCl, saturated aqueousNaHCO₃, and saturated aqueous NaCl before being dried over MgSO₄.Removal of the solvents under reduced pressure and column chromatography(10% EtOAc-hexanes) of the residue afforded the title compound as acolorless solid.

¹H NMR(CDCl₃): δ 0.09 (s, 9H), 1.15 (t, J=8.3 Hz, 2H), 1.45 (s, 6H),2.08 (t, J=7.0 Hz, 2H), 2.81 (t, J=7.0 Hz, 2H), 4.43 (t, J=8.3 Hz, 2H),7.28 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H),8.30 (dd, 1H, J=1.9, 8.3 Hz, 1H), 8.85 (d, J=1.9 Hz, 1H).

(+/−)2-Trimethylsilylethyl4-[[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E37)

A solution of 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E36, 160.0 mg, 0.365 mmol) in 2.0 mL EtOH and 2.0 mL THF wascooled to 0° C. and treated with NaBH₄ (13.8 mg, 0.365 mmol). After 3 hthe reaction was quenched by the careful addition of 5% aqueous HCl.EtOAc (100 mL) was added and the solution washed with H₂O, diluteaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure followed by columnchromatography (10-15% EtOAc) afforded the title compound.

¹H NMR (CDCl₃): δ 0.09 (s, 9H), 1.14 (t, J=8.4 Hz, 2H), 1.30 (s, 3H),1.37 (s, 3H), 1.68 (m, 1H), 1.92 (m, 2H), 2.12 (m, 1H), 4.45 (t, J=8.4Hz, 2H), 4.82 (m, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.3 Hz, 1H),8.04 (dd, J=2.0, 8.3 Hz, 1H), 8.11 (d, J=8.7 Hz, 2H), 8.30 (d, J=2.0 Hz,1H).

(+/−) 2-(Trimethylsilyl)ethyl4-[[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E38)

To a solution of (+/−) 2-trimethylsilylethyl4-[[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E37, 70.0 mg, 0.159 mmol) in 5.0 mL CH₂Cl₂ at 0° C. were addeddiisopropylethylamine (276.2 mg, 2.137 mmol), and chloromethyl methylether (37.7 mg, 0.469 mmol). The resulting solution was stirred at roomtemperature overnight. The reaction mixture was diluted with EtOAc andwashed with 5% HCl, H₂O, saturated aqueous NaHCO₃, and saturated aqueousNaCl, before being dried over MgSO₄. Removal of the solvents underreduced pressure, followed by column chromatography (10% EtOAc-hexanes)afforded the title compound as a colorless oil.

¹H NMR (CDCl₃): δ 0.09 (s, 9H), 1.14 (t, J=8.3 Hz, 2H), 1.30 (s, 3H),1.39 (s, 3H), 1.63 (m, 2H), 1.97 (m, 2H), 3.50 (s, 3H), 4.43 (t, J=8.3Hz, 2H), 4.71 (t, J=5.0 Hz, 1H), 4.81 (d, J=7.0 Hz, 1H), 4.91 d, J=7.0Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.05 (dd,J=1.8, 8.3 Hz, 1H), 8.10 (d, J=8.7 Hz, 2H), 8.19 (d, J=1.8 Hz, 1H).

(+/−)4-[[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoicacid (Compound E39)

To a solution of (+/−)2-trimethylsilylethyl-4-[[(5,5-dimethyl-5,6,7,8-tertahydro-8-(O-methoxymethyl)naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E38, 72.0 mg, 0.148 mmol) in 2.0 mL THF was addedtetrabutylammonium fluoride (130.7 mg, 0.500 mmol; 0.5 mL of a 1Msolution in THF). The resulting solution was stirred overnight at roomtemperature, diluted with EtOAc, and washed with H₂O and saturatedaqueous NaCl. The solution was dried (MgSO₄) and then concentrated underreduced pressure. The title compound was isolated as a colorless oil bypreparative TLC (5% MeOH—CH₂Cl₂).

1H MNR (acetone-d₆): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.67 (m, 1H), 1.95(m, 2H), 2.11 (m, 1H), 3.42 (s, 3H), 4.70 (t, J=5.0 Hz, 1H), 4.88 (d,J=7.0 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.3 Hz, 1H), 7.77 (d,J=7.0 Hz, 2H), 8.03 (dd, J=1.9, 8.3 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H),8.19 d, J=1.9 Hz, 1H).

(+/−) Ethyl4-[[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoicacid (Compound E40)

A solution of ethyl4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E44, 126.0 mg, 0.344 mmol) in 1.5 mL EtOH and 1.5 mL THF wascooled to 0° C. and treated with NaBH₄ (13.0 mg, 0.344 mmol). After 3 hthe reaction was quenched by the careful addition of H₂O. EtOAc (50 mL)was added and the solution washed with H₂O and saturated aqueous NaClbefore being dried over MgSO₄. Removal of the solvents under reducedpressure followed by column chromatography (15-20% EtOAc) afforded thetitle compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.41 (t, J=7.1 Hz, 3H),1.68 (m, 1H), 1.83-1.99 (m, 2H), 2.15 (m, 1H), 4.39 (q, J=7.1 Hz, 2H),4.82 (m, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.05 (dd,J=1.8, 8.3 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H), 8.29 (d, J=1.8 Hz, 1H).

(+/−)Ethyl4-[[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E41)

To a solution of (+/−) ethyl4-[[(5,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E40, 131.8 mg, 0.358 mmol) in 5.0 mL CH₂Cl₂ at 0 ° C. wasadded diisopropylethylamine (277.5 mg, 2.147 mmol), and chloromethylmethyl ether (86.9 mg, 1.08 mmol). The resulting solution was stirred atroom temperature overnight. The reaction mixture was diluted with EtOAcand washed with 10% HCl, H₂O, saturated aqueous NaHCO₃, and saturatedaqueous NaCl, before being dried over MgSO₄. Removal of the solventsunder reduced pressure, followed by column chromatography (15%EtOAc-hexanes) afforded the title compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.38 (s, 3H), 1.41 (t, J=7.1 Hz, 3H),1.62 (m, 2H), 1.96 (m, 2H), 3.50 (s, 3H), 4.39 (q, J=7.1 Hz, 2H), 4.71(t, J=5.0 Hz, 1H), 4.80 d, J=7.0 Hz, 1H), 4.92 (d, J=7.0 Hz, 1H), 7.28(d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.05 (dd, J=1.8, 8.3 Hz, 1H),8.12 (d, J=8.7 Hz, 2H), 8.19 (d, J=1.8 Hz, 1H).

2-(Trimethylsilyl)ethyl-4-[[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E42)

A mixture of 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E36, 80.0 mg, 0.182 mmol), O-methylhydroxylamine hydrochloride(22.8 mg, 0.273 mmol), and NaOAc)×3H₂O (62.0 mg, 0.455 mmol) in 3.0 mLof EtOH was stirred at room temperature for 5 days. The reaction wasdiluted with H₂O and extracted with EtOAc. The combined organic layerswere washed with H₂O and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure and columnchromatography (4-8% EtOAc-hexanes) of the residue, followed bypreparative TLC (20% EtOAc-hexanes, afforded the title compound.

¹H NMR (CDCl₃): δ 0.09 (s, 9H), 1.14 (t, J=8.6 Hz, 2H), 1.33 (s, 6H),1.76 (t, J=6.9 Hz, 2H), 2.82 (t, J=6.9 Hz, 2H), 4.04 (s, 3H), 4.43 (q,J=8.4 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.08 (dd,J=1.9, 8.3 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H), 8.78 (d, J=1.9 Hz, 1H).

4-[[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoicacid (Compound E43)

To a solution of (trimethylsilyl)ethyl4-[[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E42, 40.0 mg, 0.086 mmol) in 1.5 mL THF was addedtetrabutylammonium fluoride (68.0 mg, 0.260 mmol; 0.26 mL of a 1Msolution in THF). The resulting solution was stirred for 6 h at roomtemperature, diluted with EtOAc, and washed with H₂O and saturatedaqueous NaCl. The solution was dried (MgSO₄) and then concentrated underreduced pressure. The title compound was isolated as a colorless oil bypreparative TLC (5% MeOH-CH₂Cl₂).

¹H NMR (acetone-d₆): δ 1.34 (s, 6H), 1.78 (t, J=7.0 Hz, 2H), 2.81 (t,J=7.0 Hz, 2H), 3.98 (s, 3H), 7.45 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.3 Hz,1H), 8.10 (dd, J=1.9, 8.3 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H), 8.74 (d,J=1.9 Hz, 1H).

Ethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44)

To a solution of5,5-dimethyl-5,6-dihydro-8(7H)-one-2-naphthalenecarboxylic acid(Compound E3, 270.0 mg, 1.24 mmol), ethyl 4-hydroxybenzoate (226.0 mg,1.364 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(309.0 mg, 1.61 mmol), and 4-N,N-dimethylaminopyridine (197.0 mg, 1.61mmol) in 5.0 mL DMF was stirred at room temperature overnight. EtOAc (25mL) was added and the solution washed with H₂O, 1M HCl, and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure and column chromatography (7% EtOAc-hexanes) ofthe residue afforded the title compound as a pale-orange solid.

¹H NMR(CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 1.45 (s, 6H), 2.08 (t, J=6.7Hz, 2H), 2.80 (t, J=6.7 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.30 (d, J=8.7Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.7 Hz, 2H), 8.31 (dd,J=1.8, 8.4 Hz, 1H) 8.04 (d, J=1.8 Hz, 1H).

Ethyl4-[[(5,5-dimethyl-8(72)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E46)

A mixture of ethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44, 66.0 mg, 0.180 mmol), O-methylhydroxylamine hydrochloride(23.0 mg, 0.270 mmol), and NaOAc)3H₂O (62.0 mg, 0.455 mmol) in 3.0 mL ofEtOH was stirred at room temperature for 6 days. The reaction wasdiluted with H₂O and extracted with EtOAc. The combined organic layerswere washed with H₂O and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure and columnchromatography (4-8% EtOAc-hexanes) of the residue, followed bypreparative TLC (5% EtOAc-hexanes) afforded the title compound.

¹H NMR (CDCl₃): δ 1.33 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 1.76 (t, J=6.9Hz, 2H), 2.82 (t, J=6.9 Hz, 2H), 4.03 (s, 3H), 4.39 (q, J=7.1 Hz, 2H),7.30 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.3 Hz, 1H), 8.11 (dd, J=1.9, 8.3 Hz,1H), 8.13 (d, J=8.6 Hz, 2H), 8.78 (d, J=1.9 Hz, 1H).

(+/−) Ethyl2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound E47)

To a suspension of Zn (1.20 g, 18.4 mmol) in 10 mL benzene at 100° C.was slowly added a solution of ethyl 2-bromoacetate (658.0 mg, 3.94mmol) and 3,4-dihydro-4,4-dimethyl-7-bromo-naphthalen-1(2H)-one(Compound G, 500.0 mg, 1.97 mmol) in 20.0 mL benzene. The resultingmixture was heated for 2 h, cooled to room temperature, and the solutiondecanted from a the residual solids. The solids were washed with EtOAcand the combined organic layers were washed with cold 15% H₂SO₄,saturated aqueous NaHCO₃, and saturated aqueous NaCl before being driedover MgSO₄. Removal of the solvents under reduced pressure and columnchromatography (10% EtOAc-hexanes) afforded the title compound as ayellow oil.

¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.29 (s, 3H), 1.31 (t, J=7.1 Hz, 3H),1.62-1.82 (m, 2H), 2.05 (m, 2H), 2.75 (s, 2H), 4.21 (q, J=7.1 Hz, 2H),7.16 (d, J=8.5 Hz, 1H), 7.33 (dd, J=2.1, 8.5 Hz, 1H), 7.71 (d, J=2.1 Hz,1H).

(+/−) Ethyl2-(1-acetoxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound E48)

To a solution of (+/−) ethyl2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound E47, 200.0 mg, 0.586 mmol) and 4-N,N-dimethylaminopyridine(86.0 mg, 0.703 mmol) in 4.0 mL CH₂Cl₂ at 0° C. was added aceticanhydride (239.3 mg, 2.344 mmol). The resulting solution was warmed toroom temperature and stirred overnight. The reaction was warmed to 50°C. for 3 h, cooled to room temperature, and diluted with EtOAc (70 mL).The solution was washed with H₂O, saturated aqueous NaHCO₃, 10% aqueousHCl, and saturated aqueous NaCl, before being dried over MgSO₄. Removalof the solvents under reduced pressure followed by column chromatographyafforded the title compound as a colorless oil.

¹H NMR (CDCl₃): δ 1.23 (t, J=7.1 Hz, 3H), 1.30 (s, 3H), 1.31 (s, 3H),1.76 (t, J=6.9 Hz, 2H), 2.05 (s, 3H), 2.48 (m, 1H), 2.67 (m, 1H), 3.03(s, 2H), 4.12 (q, J=7.1 Hz, 2H), 7.19 (d, J=8.5 Hz, 1H), 7.33 (dd,J=2.1, 8.5 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H).

(+/−) Ethyl4-[(5,5-dimethyl-5,6,7,8-tetrahydro-8-acetoxy-8-carbethoxymethyl-naphthalen-2-yl)carboxamido]-benzoate(Compound E49)

A solution of ethyl2-(1-acetoxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound E48, 450.0 mg, 1.23 mmol), ethyl 4-aminobenzoate (810.0 mg,4.90 mmol), 1,3-bis(diphenylphosphino)propane (100.0 mg, 0.245 mmol) in5.0 mL Et₃N, and 10.0 mL DMSO was sparged with CO (g) for 10 minutes. Tothis solution was added bis(triphenylphosphine)palladium(II) chloride(105.0 mg, 0.150 mmol). The solution was placed under 1 atm of CO(balloon) and heated to 75° C. for 4 days. Upon cooling to roomtemperature the mixture was diluted with EtOAc and the solution washedwith 10% HCl, H₂O, and saturated aqueous NaCl before being dried overNa₂SO₄. Removal of the solvents under reduced pressure and columnchromatography (5-25% EtOAc-hexanes) afforded the title compound.

¹H NMR (CDCl₃): δ 1.20 (t, J=7.1 Hz, 3H), 1.35 (s, 6H), 1.40 (t, J=7.1Hz, 3H), 1.78 (m, 2H), 2.03 (s, 3H), 2.50 (m, 1H), 2.71 (m, 1H), 3.12(m, 2H), 4.11 (q, J=7.1 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.42 (d, J=8.2Hz, 1H), 7.70 (dd, J=1.9, 8.2 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.95 (d,J=1.9 Hz, 1H), 8.04 (d, J=8.7 Hz, 2H), 8.20 (s, 1H).

Ethyl(E)-4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50a(trans)) Ethyl(Z)-4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50a(cis)) and Ethyl(E)-4-[[(55-dimethyl-5,6-dihydro-8-(carbethoxymethyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50b)

To a solution of (+/−) ethyl4-[(5,5-dimethyl-5,6,7,8-tertahydro-8-acetoxy-8-carbethoxymethyl-naphthalen-2-yl)carboxamido]-benzoate(Compound E49, 210.0 mg, 0.438 mmol) in 6.0 mL CH₂Cl₂ was added1,8-diazobicyclo[5.4.0]undec-7-ene (200.0 mg, 1.314 mmol). The resultingsolution was stirred at room temperature for 21 h, diluted with EtOAc,and the combined solution washed with 10% aqueous HCl and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure and column chromatography (15% EtOAc-hexanes)afforded pure (Compound 50b)and a mixture of Compound E50a(trans) andCompound E50a(cis). Compound E50a(trans) and Compound E50a(cis) wereisolated using reverse phase HPLC (5% H₂O—CH₃CN), each as a colorlesssolid.

Compound E50a(trans):

¹H NMR (CDCl₃): δ 1.30 (s, 6H), 1.31 (t, J=7.1 Hz, 3H), 1.40 (t, J=7.1Hz, 3H), 1.73 (t, J=6.1 Hz, 2H), 3.21 (t, J=6.1 Hz, 2H), 4.16 (q, J=7.1Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 6.35 (s, 1H), 7.46 (d, J=8.1 Hz, 1H),7.78 (d, J=8.7 Hz, 2H), 7.82 (dd, J=1.8, 8.1 Hz, 1H), 8.04 (d, J=8.7 Hz,2H), 8.06 (d, J=1.8 Hz, 1H), 8.41 (s, 1H).

Compound E50a(cis):

¹H NMR (CDCl₃): δ 1.31 (t, J=7.1 Hz, 3H), 1.34 (s, 6H), 1.40 (t, J=7.1Hz, 3H), 1.88 (t, J=6.5 Hz, 2H), 2.61 (t, J=6.5 Hz, 2H), 4.21 (q, J=7.1Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 5.92 (t, J=1.1 Hz, 1H), 7.46 (d, J=8.2Hz, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.88 (dd, J=1.9, 8.2 Hz, 1H), 8.06 (d,J=8.7 Hz, 2H), 8.39 (s, 1H).

(Compound E50b):

¹H NMR (CDCl₃): δ 1.19 (t, J=7.1 Hz, 3H), 1.28 (s, 6H), 1.39 (t, J=7.1Hz, 3H), 2.26 (d, J=4.5 Hz, 2H), 3.49 (s, 2H), 4.11 (q, J=7.1 Hz, 2H),4.38 (q, J=7.1 Hz, 2H), 5.97 (t, J=4.5 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H),7.70 (dd, J=1.8, 8.0 Hz, 1h), 7.74 (m, 3H), 8.00 (d, J=8.7 Hz, 2H), 8.41(s, 1H).

(Z)-4-[[(5,5-Dimethyl-5,6-dihydro-8(7H)-(carboxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoicacid (Compound E52)

A solution of ethyl(Z)-4-[(5,5-dimethyl-5,6-dihydro-8(7H)-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50a(cis), 15.0 mg, 0.034 mmol) and NaOH (80.0 mg, 2.00 mmol;2.0 mL of a 1M aqueous solution) in 2.0 mL EtOH and 1.0 mL THF wasstirred overnight at room temperature. The reaction was quenched by theaddition of 10% HCl and extracted with EtOAc. The combined organiclayers were washed with H₂O and saturated aqueous NaCl, and dried overNa₂SO₄. Removal of the solvents under reduced pressure andcrystallization from CH₃CN afforded the title compound as a colorlesssolid.

¹H NMR (acetone-d6): δ 1.35 (s, 6H), 1.87 (t, j=6.6 Hz, 2H), 2.61 (m,2H), 5.91 (t, J=1.3 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.91-8.04 (m, 5H),8.29 (d, J=1.9 Hz, 1H), 9.66 (s, 1H).

(E)-4-[[(5,5-Dimethyl-5,6-dihydro-8(7H)-(carboxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoicacid (Compound E53)

A solution of ethyl(E)-4-[(5,5-dimethyl-5,6-dihydro-8(7H)-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50a(trans), 20.0 mg, 0.046 mmol) and NaOH (160.0 9 mg, 4.00mmol; 4.0 mL of a 1M aqueous solution) in 3.0 mL EtOH and 1.0 mL THF wasstirred overnight at room temperature. The reaction was quenched by theaddition of 10% HCl and extracted with EtOAc. The combined organiclayers were washed with H₂O and saturated aqueous NaCl, and dried overNa₂SO₄. Removal of the solvents under reduced pressure andcrystallization from CH₃CN afforded the title compound as a colorlesssolid.

¹H NMR (acetone-d₆): δ 1.34 (s, 6H), 1.76 (t, J=6.9 Hz, 2H), 3.24 (m,2H), 6.46 (t, J=1.8 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.95-8.05 (m, 5H),8.29 (d, J=1.9 Hz, 1H), 9.91 (s, 1H).

(+/−) Ethyl4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyloxy]benzoate(Compound E54)

To a suspension of Zn (500.0 mg, 7.65 mmol) in 10 mL benzene at 100° C.was slowly added a solution of ethyl 2-bromoacetate (150.3 mg, 0.900mmol) and ethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44, 110.0 mg, 0.300 mmol) in 10.0 mL benzene. The resultingmixture was heated for 2 h, cooled to room temperature, and the solutiondecanted from the residual solids. The solids were washed with EtOAc andthe combined organic layers washed with cold 15% H₂SO₄, saturatedaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure and columnchromatography (15% EtOAc-hexanes) afforded the title compound as apale-yellow oil.

¹H NMR (CDCl₃): δ 1.30 (t, J=7.1 Hz, 3H), 1.33 (s, 3H), 1.37 (s, 3H),1.43 (t, J=7.1 Hz, 3H), 1.72-1.90 (m, 211), 2.11 (m, 2H), 2.84 (m, 211),4.23 (q, J=7.1 Hz, 2H), 4.31 (s, 1H), 4.39 (q, J=7.1 Hz, 2H), 7.27 (d,J=8.8 Hz, 2H), 7.46 (d, J=8.3 Hz, 1H), 8.03 (dd, J=1.8, 8.3 Hz, 1H),8.12 (d, J=8.8 Hz, 2H), 8.43 (d, J=1.8 Hz, 1H).

Ethyl4-[[(5,5-dimethyl-8-(carbethoxy)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E55)

To a solution of (+/−) ethyl4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E54, 35.0 mg, 0.077 mmol) in 10 mL benzene was added acatalytic amount (approximately 2 mg) of p-toluenesulfonic acidmonohydrate. The solution was heated to reflux under a Dean-Stark trapfor 3 h, and then cooled to room temperature and stirred overnight. Thesolvent was removed under reduced pressure and the title compoundisolated from the residue by column chromatography (10% EtOAc-hexanes).

¹H NMR (CDCl₃): δ 1.21 (t, J=7.1 Hz, 3H), 1.33 (s, 6H), 1.41 (t, J=7.1Hz, 3H), 2.31 (d, J=4.6 Hz, 2H), 3.54 (s, 2H), 4.14 (q, J=7.1 Hz, 2H),4.39 (q, J=7.1 Hz, 2H), 6.01 (t, J=4.6 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H),7.46 (d, J=8.1 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H), 8.04 (dd, J=1.7, 8.1 Hz,1H), 8.13 (d, J=8.7 Hz, 2H).

Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE56a) and Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE56b)

To a solution of ethyl 4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E40, 243 mg,0.66 mmol) in anhydrous CH₂Cl₂ (10 mL) was added 3,4-dihydro-2H-pyran(184 mg, 2.2 mmol) followed by pyridinium p-toluenesulfonate (26 mg, 0.1mmol). The reaction mixture was stirred at ambient temperature for 16 h,and diluted with CH₂Cl₂ (20 mL). The mixture was washed successivelywith water (5 mL), saturated NaHCO₃ (10 mL), water (10 mL) and brine (10mL). The organic phase was dried over MgSO₄ and then concentrated invacuo to a pale yellow oil. Purification by flash column chromatography(silica, 20% EtOAc-hexane) followed by HPLC separation (partisil 10, 10%EtOAc-hexane) afforded the title compounds as colorless oil.

Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE56a)

¹H NMR (CDCl₃): δ 1.28 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz, 3H),1.51-2.11(m, 10H), 3.54-3.61 (m, 1H), 3.96-4.03 (m, 1H), 4.35 (q, J=7.1Hz, 2H), 4.70 (t, J=5.0 Hz, 1H), 4.87 (t, J=2.3 Hz, 1H), 7.28 (d, J=8.3Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 8.02 (dd, J=1.9, 8.3 Hz, 1H), 8.10-8.13(m, 3H).

Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE56b)

¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz, 3H),1.58-2.10(m, 10H), 3.57-3.63 (m, 1H), 4.01-4.08 (m, 1H), 4.35 (q, J=7.1Hz, 2H), 4.82 (t, J=4.5 Hz, 1H), 4.93 (t, J=3.6 Hz, 1H), 7.26 (d, J=8.3Hz, 2H), 7.44 (d, J=8.2 Hz, 1H), 8.01 (dd, J=1.9, 8.3 Hz, 1H), 8.10 (d,J=8.6 Hz, 2H), 8.37 (d, J=1.8 Hz, 1H).

Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE58a) and Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE58b)

Employing the same general procedure as for the preparation of ethyl4-[5,6,7,8-tetrahydro-8(R or S)-2(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-2(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate, ethyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E40, 222 mg,0.6 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10, 10% EtOAc-hexane) afforded the title compounds ascolorless oils.

Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE58a):

¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz, 3H),1.52-2.15(m, 10H), 3.54-3.61 (m, 1H), 3.96-4.03 (m, 1H), 4.35 (q, J=7.1Hz, 2H), 4.70 (t, J=5.0 Hz, 1H), 4.87 (t, J=2.3 Hz, 1H), 7.26 (d, J=8.3Hz, 2H), 7.46 (d, J=8.3 Hz, 1H), 8.02 (dd, J=1.9, 8.3 Hz, 1H), 8.10-8.13(m, 3H).

Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-naphthoyloxy]benzoate (CompoundE58b)

¹H NMR (CDCl₃): δ 1.32 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz, 3H),1.57-2.10(m, 10H), 3.57-3.64 (m, 1H), 4.01-4.08 (m, 1H), 4.35 (q, J=7.1Hz, 2H), 4.82 (t, J=4.5 Hz, 1H), 4.94 (t, J=3.6 Hz, 1H), 7.26 (d, J=8.3Hz, 2H), 7.44 (d, J=8.2 Hz, 1H), 8.00 (dd, J=1.9, 8.3 Hz, 1H), 8.10 (d,J=8.6 Hz, 2H), 8.36 (d, J=1.8 Hz, 1H).

Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60a) and Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60b)

Employing the same general procedure as for the preparation of ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate, benzyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E82, 142 mg,0.3 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10 PAC, 10% EtOAc-hexane) afforded the title compounds ascolorless oil.

Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (Compound 60a)

¹H NMR (CDC₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.54-2.16 (m, 10H),3.55-3.63 (m, 1H), 3.98-4.05 (m, 1H), 4.72 (t, J=4.9 Hz, 1H), 4.89 (t,J=4.6 Hz, 1H), 5.39 (s, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.31-7.50 (m, 6H),8.03 (dd, J=1.9, 8.3 Hz, 1H), 8.12-8.18 (m, 3H).

Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60b)

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.35 (s, 3H), 1.54-2.08 (m, 10H),3.57-3.64 (m, 1H), 4.01-4.08 (m, 1H), 4.82 (t, J=4.4 Hz, 1H), 4.94 (t,J=3.9 Hz, 1H), 5.37 (s, 2H), 7.27 (d, J=6.8 Hz, 2H), 7.34-7.47 (m, 6H),8.00 (dd, J=2.0, 8.3 Hz, 1H), 8.10 (d, J=9.2 Hz, 2H), 8.36 (d, J=1.9 Hz,1H).

Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62a) and Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62b)

Employing the same general procedure as for the preparation of ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate, benzyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E82, 142 mg,0.3 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10 PAC, 10% EtOAc-hexane) afforded the title compounds ascolorless oils. Separation of the diastereomers gave a 1:1 ratio of thetitle compounds both as colorless oils (RT=32 minutes and 39 minutes),respectively.

Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62a)

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.52-2.15 (m, 10H),3.54-3.61 (m, 1H), 3.96-4.03 (m, 1H), 4.70 (t, J=5.0 Hz, 1H), 4.87 (t,J=4.5 Hz, 1H), 5.37 (s, 2H), 7.26 (d, J=6.7 Hz, 2H), 7.29-7.49 (m, 6H),8.02 (dd, J=1.9, 8.3 Hz, 1H), 8.10-8.17 (m, 3H).

Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E62b)

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.35 (s, 3H), 1.54-2.10 (m, 10H),3.57-3.64 (m, 1H), 4.01-4.08 (m, 1H), 4.82 (t, J=4.7 Hz, 1H), 4.94 (t,J=3.5 Hz, 1H), 5.37 (s, 2H), 7.27 (d, J=6.8 Hz, 2H), 7.34-7.47 (m, 6H),8.00 (dd, J=2.0, 8.3 Hz, 1H), 8.10 (d, J=9.2 Hz, 2H), 8.36 (d, J=1.9 Hz,1H).

4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE64)

To a solution of benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60a, 15 mg, 0.03 mmol) in ethyl acetate, (5 mL) was added a catalyticamount of 10% Pd/C. The reaction mixture was then placed under a blanketof H₂ by using a H₂ balloon and stirred at ambient temperature for 12 h.The reaction mixture was then filtered through a plug of MgSO₄ and thefiltrate was concentrated under reduced pressure to give a white solid.Recrystallization from acetonitrile gave the title compound as a whitesolid.

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.51-2.17 (m, 10H),3.57-3.64 (m, 1H), 3.98-4.06 (m, 1H), 4.72 (t, J=4.9 Hz, 1H), 4.90 (t,J=4.6 Hz, 1H), 7.31 (dd, J=2.5,9.3 Hz, 2H), 7.48 (d, j=8.3 Hz, 1H), 8.04(dd, J=1.9, 8.3 Hz, 1H), 8.13 (d, J=1.7 Hz, 1H), 8.17 (dd, j=2.4, 9.3Hz, 2H).

4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE65)

Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE64), benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60b, 15 mg, 0.03 mmol) was converted to the title compound (whitesolid).

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.36 (s, 3H), 1.55-2.11 (m, 10H),3.59-3.64 (m, 1H), 4.02-4.10 (m, 1H), 4.83 (t, J=5.0 Hz, 1H), 4.95 (t,J=3.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.4 (d, J=8.3 Hz, 1H), 8.01 (dd,J=1.8, 8.2 Hz, 1H), 8.16 (d, J=8.6 Hz, 2H), 8.37 (d, J=2.0 Hz, 1H).

4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE66)

Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE64), benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62a, 15 mg, 0.03 mmol) was converted to the title compound (whitesolid).

¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.36 (s, 3H), 1.53-2.15 (m, 10H),3.56-3.63 (m, 1H), 3.97-4.04 (m, 1H), 4.71 (t, J=4.9 Hz, 1H), 4.89 (t,J=4.3 Hz, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 1H), 8.03 (dd,J=1.9, 8.2 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.6 Hz, 2H).

4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE67)

Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE64) benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62b, 15 mg, 0.03 mmol) was converted to the title compound (whitesolid).

¹H NMR (CDCl₃): δ 1.31 (s, 3H), 1.37 (s, 3H), 1.55-2.09 (m, 10H),3.60-3.65 (m, 1H), 4.04-4.10 (m, 1H), 4.85 (t, J=4.8 Hz, 1H), 4.96 (t,J=3.8 Hz, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.3 Hz, 1H), 8.03 (dd,J=1.9, 8.2 Hz, 1H), 8.18 (d, J=8.6 Hz, 2H), 8.38 (d, J=1.7 Hz, 1H).

Ethyl 4-[5,6,7.8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70a) and Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70b)

Employing the same general procedure as for the preparation of ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-7napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-7-napthoyloxy]benzoate, (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E32, 142 mg, 0.3 mmol) was converted to a mixture ofdiastereomers using 3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) andpyridinium p-toluenesulfonate (26 mg, 0.1 mmol). Purification by flashcolumn chromatography (silica, 20% EtOAc-hexane) followed by HPLCseparation (partisil 10 PAC, 20% EtOAc-hexane) of the diastereomers gavea 1:1 ratio of the title compounds, both as colorless oil (RT=53 minutesand 60 minutes), respectively.

Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70a)

¹H NMR (CDCl₃): δ 1.24 (s, 3H), 1.30 (s, 3H), 1.34 (t, J=7.1 Hz, 3H),1.48-2.10 (m, 10H), 3.52-3.56 (m, 1H), 3.92-3.98 (m, 1H), 4.30 (t, J=7.1Hz, 2H), 4.61 (t, J=4.8 Hz, 1H), 4.80 (t, J=4.5 Hz, 1H), 7.36 (d, J=8.2Hz, 1H), 7.68-7.74 (m, 3H), 7.80 (d, J=1.9 Hz, 1H), 7.98 (d, J=8.7 Hz,2H), 8.28 (s, 1H).

Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70b)

¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.32 (s, 3H), 1.36 (t, J=7.1 Hz, 3H),1.58-2.04 (m, 10H), 3.57-3.61 (m, 1H), 4.00-4.05 (m, 1H), 4.31 (t, J=7.1Hz, 2H), 4.78 (t, J=4.9 Hz, 1H), 4.86 (t, J=4.6 Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 7.73-7.75 (m, 3H), 8.00-8.03 (m, 3H), 8.34 (s, 1H).

Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72a) and Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72b)

Employing the same general procedure as for the preparation of ethyl4-[5,6,7,8-tetrahydro-8-(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-7-napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-7-napthoyloxy]benzoate, ethyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate (CompoundE32, 142 mg, 0.3 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10 PAC, 20% EtOAc-hexane) afforded the title compounds ascolorless oil.

Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72a)

¹H NMR (CDCl₃): δ 1.25 (s, 3H), 1.32 (s, 3H), 1.35 (t, J=7.1 Hz, 3H),1.54-2.10 (m, 10H), 3.53-3.60 (m, 1H), 3.94-4.01 (m, 1H), 4.31 (t, J=7.1Hz, 2H), 4.64 (t, J=4.9 Hz, 1H), 4.83 (t, J=4.3 Hz, 1H), 7.39 (d, J=8.2Hz, 1H), 7.68-7.73 (m, 3H), 7.80 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.7 Hz,2H), 8.12 (s, 1H).

Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72b)

¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.34 (s, 3H), 1.37 (t, J=7.1 Hz, 3H),1.56-2.10 (m, 10H), 3.58-3.65 (m, 1H), 4.01-4.08 (m, 1H), 4.33 (t, J=7.1Hz, 2H), 4.81 (t, J=4.9 Hz, 1H), 4.88 (t, J=4.6 Hz, 1H), 7.42 (d, J=8.3Hz, 1H), 7.72-7.78 (m, 3H), 8.02-8.07 (m, 3H), 8.11 (s, 1H).

4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E74)

To a solution of ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70a, 54 mg, 0.12 mmol) in THF (2 mL) and methanol (1 mL) wasadded 0.5 M lithiumhydroxide (2 mL, 1 mmol). The reaction mixture wasstirred at ambient temperature for 12 h. The reaction mixture wasdiluted with EtOAc (15 mL), and acidified with 10% HCl to pH 4. Theorganic layer was washed with water (5 mL), brine (10 mL), dried (MgSO₄)and the solvent removed under reduced pressure. Recrystallization fromEtOAc/hexane afforded the title compound as a white solid.

¹H NMR (acetone-d₆): δ 1.27 (s, 3H), 1.33 (s, 3H), 1.49-2.11 (m, 10H),2.80 (br, 1H), 3.51-3.58 (m, 1H), 3.89-3.96 (m, 1H), 4.67 (t, J=4.4 Hz,1H), 4.89 (t, J=4.5 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.80 (d, J=1.9 Hz,1H), 7.91-8.04 (m, 5H), 9.73 (s, 1H).

4-[5,6.7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E75)

Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E74) ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoate(Compound E70b, 36 mg, 0.08 mmol) was converted into the title compound(white solid).

¹H NMR (acetone-d₆): δ 1.28 (s, 3H), 1.34 (s, 3H), 1.51-2.02 (m, 10H),2.80 (br, 1H), 3.55-3.60 (m, 1H), 3.96-4.03 (m, 1H), 4.77 (t, J=5.4 Hz,1H), 4.92 (t, J=3.8 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.82 (dd, J=2.0,8.3 Hz, 1H), 7.97-8.02 (m, 4H), 8.09 (d, J=1.9 Hz, 1H), 9.77 (s, 1H).

4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E76)

Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E74), ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoate(Compound E72b, 36 mg, 0.08 mmol) was converted into the title compound(white solid).

¹H NMR (CDCl₃): δ 1.28 (s, 3H), 1.34 (s, 3H), 1.55-2.08 (m, 10H),3.59-3.65 (m, 1H), 4.04-4.12 (m, 1H), 4.82 (t, J=4.9 Hz, 1H), 4.88 (t,J=2.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.74-7.81 (m, 3H), 8.02 (d, J=1.8Hz, 1H), 8.06 (d, J=8.7 Hz, 2H), 8.30 (s, 1H).

4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]BenzoicAcid (Compound E77)

Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E74), ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoate(Compound E72a, 36 mg, 0.08 mmol) was converted into the title compound(white solid).

¹H NMR (CDCl₃): δ 1.27 (s, 3H), 1.34 (s, 3H), 1.55-2.13 (m, 10H),3.57-3.63 (m, 1H), 3.97-4.03 (m, 1H), 4.70 (t, J=4.7 Hz, 1H), 4.89 (t,J=2.4 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.72-7.77 (m, 3H), 7.82 (d, J=1.9Hz, 1H), 8.06-8.10 M, 3H).

5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenecarboxylicacid (Compound E78)

A solution of7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C42, 450.0 mg, 1.54 mmol) in 20 mL of THF was cooled to −78°C. and 197.3 mg (3.08 mmol; 1.8 mL of a 1.7M solution in pentane) addedgiving a pale-yellow solution. After 1 h, CO2 (from evaporation of DryIce, dried with CaSO₄) was bubbled through the solution for 1 h. Afterstirring at −78° C. for an additional hour, the reaction was quenchedwith 10% aqueous HCl. The solution was extracted with EtOAc and thecombined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over Na₂SO₄. Removal of the solvents under reducedpressure, and washing of the residue with hexanes afforded the titlecompound as a colorless solid.

¹H NMR (CDCl₃) δ : 1.25 (6H, s), 1.38 (9H, s), 2.17 (2H, d, J=4.9 Hz),6.02 (1H, t, J=4.9 Hz), 7.41 (1H, d, J=8.1 Hz), 7.91 (1H, dd, J=1.6, 8.1Hz), 8.42 (1H, d, J=1.6 Hz).

Ethyl4-[(5,5-dimethyl-5,6-dihydro-8-(1.1-dimethylethyl)-2-naphthalenyl)carboxamido]-benzoate(Compound E79)

A solution of5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenecarboxylicacid (Compound E78, 150.0 mg, 0.581 mmol), ethyl 4-aminobenzoate (115.2mg, 0.697 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (145.0 mg, 0.755 mmol), and 4-N,N-dimethylaminopyridine(89.0 mg, 0.697 mmol) in 8.0 mL DMF was stirred overnight at roomtemperature. EtOAc (110 mL) was added and the solution washed with H₂O,5% HCl, saturated aqueous NaHCO₃, and saturated aqueous NaCl beforebeing dried over MgSO₄. Removal of the sovents under reduced pressureand column chromatography (10-25% EtOAc-hexanes) of the residual oilafforded the title compound as a colorless solid.

¹H NMR(CDCl₃) δ 1.25 (6H, s), 1.39 (9H, s), 1.40 (3H, t, J=7.1 Hz), 2.18(2H, d, J=4.9 Hz), 4.37 (2H, q, J=7.1 Hz), 6.05 (1H, t, J=4.9 Hz), 7.41(1H, d, J=8.0 Hz), 7.58 (1H, dd, J=1.8, 8.0 Hz), 7.24 (2H, d, J=8.7 Hz),7.91 (1H, s, ), 8.06 (2H, d, J=8.7 Hz), 8.26 (1H, d, J=1.8 Hz).

4-[(5,5-dimethyl-5,6-dihydro-8-(1.1-dimethylethyl)-2-naphthalenyl)carboxamido]-benzoicacid (Compound 80)

To a solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenyl)carboxamido]-benzoate(Compound E79, 50.0 mg, 0.123 mmol) in 2.0 mL of EtOH and 3.0 mL THF wasadded NaOH (240.0 mg, 6.00 mmol; 3.0 mL of a 2N aqueous solution). Afterstirring overnight at room temperature the reaction was quenched by theaddition of 1M aqueous HCl. The mixture was extracted with EtOAc and thecombined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over Na₂SO₄. Removal of the solvents under reducedpressure afforded the title compound as a colorless solid.

¹H NMR(d₆-acetone) δ 1.24 (6H, s), 1.38 (9H, s), 2.17 (2H, d, J=4.9 Hz),6.08 (1H, t, J=4.9 Hz), 7.45 (1H, d, J=8.1 Hz), 7.81 (1H, dd, J=1.8, 8.1Hz), 7.97-8.05 (4H, m), 8.31 (1H, d, J=1.8 Hz).

Benzyl-4-[[(5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E81)

To a solution of5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphthalen-2-carboxylic acid(Compound E3, 386 mg, 1.77 mmol) in dimethylformamide (4 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarboimide hydrochloride (440 mg, 2.3mmol) followed by dimethylamino pyridine (DMAP) (280 mg, 2.3 mmol). Themixture was stirred for 10 minutes, and benzyl 4-hydroxy benzoate (426mg, 1.9 mmol) was added and stirred at ambient temperature for 16 hours.The mixture was diluted with ethyl acetate (100 mL) and washed withwater (10 mL), brine (10 mL), dried and solvent distilled off. The titlecompound was obtained as a pale yellow solid after chromatographicpurification.

¹H NMR (CDC₃): δ 1.42 (s, 6H), 2.05 (t, J=6.7 Hz, 2H), 2.77 (t, J=6.7Hz, 2H), 5.37 (s, 2H), 7.25-7.50 (m, 7H), 7.58 (d, J=8.3 Hz, 1H), 8.15(d, J=8.1 Hz, 2H), 8.28 (dd, J=1.9, 8.3 Hz, 1H), 8.82 (d, J=1.9 Hz, 1H).

Benzyl-4-[[5,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-yl)carbonyloxy]-benzoate(Compound E82)

To a solution ofbenzyl-4-[[5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphthalen-2-yl)carbonyl]oxy]-benzoate((Compound E81, 377 mg, 0.88 mmol) in dimethoxyethane (20 mL) was addedsodiumborohydride (33 mg, 0.9 mmol). The mixture was stirred for 12hours at room temperature. The mixture was diluted with ethylacetate (50mL), washed with water (10 mL), brine (10 mL), dried and solventdistilled off. The title compound was obtained as a white solid afterchromatographic purification.

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.60-1.75 (m, 1H),1.85-2.00 (m, 2H), 2.05-2.20 (m, 1H), 2.30 (brs, 1H), 4.81 (t, J=5.6,1H), 5.38 (s, 2H), 7.27 (d, J=8.7 Hz, 2H), 7.35-7.51 (m, 6H), 8.04 (dd,J=1.9, 8.3 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H), 8.31 (d, J=1.9 Hz).

What is claimed is:
 1. A compound of the formula

wherein X₁ is (C(R₁)₂)_(n) where R₁ is independently H or alkyl of 1 to6 carbons, and n is an integer between 0 and 2; Z is —CO—CR₁═CR₁—; R₂ ishydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,or alkylthio of 1 to 6 carbons; R₃ is hydrogen, lower alkyl of 1 to 6carbons or F; m is an integer having the value of 0-3; o is an integerhaving the value of 0-3; Y is heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, saidheteroaryl groups being optionally substituted with one or two R₂groups; A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebond; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or trimethylsilylalkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons;, and R¹⁴ is (R₁₅)_(r)-substituted alkyl of 1-6 carbons,(R₁₅)_(r)-substituted alkenyl of 1-6 carbons and 1 or 2 double bonds,(R₁₅)_(r)-substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds,(R₁₅)_(r)-phenyl, (R₁₅)-naphthyl, (R₁₅)_(r)-heteroaryl where theheteroaryl group has 1 to 3 heteroatoms selected from the groupconsisting of O, S and N, or R₁₄ is (CH₂)_(p)CO₂H or (CH₂)_(p)CO₂R₈where p is integer between 0 to 10, r is an integer having the values of0-5, and R₁₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈.NR₈CON(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈ an alkyl group having 1 to10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, analkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynylgroup having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilylor trialkylsilyloxy group where the alkyl groups independently have 1 to6 carbons.
 2. (amended) A compound in accordance with claim 1 wherein Yis selected from the group consisting of pyridyl, thienyl and furyl. 3.A compound in accordance with claim 1 where n is
 1. 4. (twice amended) Acompound in accordance with claim 1 where n is 0 or
 1. 5. A compound inaccordance with claim 1 where A is (CH₂)_(q).
 6. A compound inaccordance with claim 1 where B is COOH or a pharmaceutically acceptablesalt thereof, COOR₈, or CONR₉R₁₀.
 7. (twice amended) A compound of theformula

where R₁ is independently H or alkyl of 1 to 6 carbons; Z is—CO—CR₁═CR₁—; R₂ is hydrogen, lower alkyl of 1 to 6 carbons; R₃ ishydrogen, lower alkyl of 1 to 6 carbons or F; m is an integer having thevalue of 0-3; o is an integer having the value of 0-4; Y is pyridyl orthienyl; A is (CH₂)_(q) where q is 0-5, lower branched chain alkylhaving 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable saltthereof COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons, and R₁₄ is alkyl of 1-6 carbons, CH₂COOH,CH₂COOR₈ or (R₁₅)_(r)-heteroaryl where the heteroaryl group has 1 to 3heteroatoms selected from the group consisting of O, S and N, r is aninteger having the values of 0-5, and R₁₅ is independently H, F, Cl, Br,I, NO₂, N(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈, an alkyl group having 1to 10 carbons, or fluoro substituted alkyl group having 1 to 10 carbons.8. A compound in accordance with claim 7 where A is (CH₂)_(q) where q is0 and where B is COOH or a pharmaceutically acceptable salt thereof,COOR₈, or CONR₉R₁₀.
 9. A compound in accordance with claim 7 where theR₁₄ group is 2-thienyl or 2-thiazolyl.
 10. A compound in accordance withclaim 7 where the R₁₄ group is tertiary butyl.
 11. A compound inaccordance with claim 7 where the R₁₄ group is CH₂COOH or CH₂COOR₈. 12.A compound in accordance with claim 11 where the Z group is connected tothe 3-position of the dihydronaphthalene ring.